.) 1991 Oxford University Press
Nucleic Acids Research, Vol. 19, Supplement 2045
Site-specific methylation: effect on DNA modification
methyltransferases and restriction endonucleases
Michael Nelson and Michael McClelland*
California Institute of Biological Research, 11099 North Torrey Pines Road, La Jolla, CA 92037 USA
INTRODUCTION
We present in Table I an updated list of the sensitivities of over
240 restriction endonucleases to the site-specific DNA
modifications '14C, n-6C, h1"5C, and m6A, four modifications that
are common in DNA prokaryotes, eukaryotes, and their viruses
(Mc2,Mc5,Mc8,Mcl 1 ,Ne3,Ne4).
Table II is a list of over 130 characterized DNA
methyltransferases. A detailed list of cloned restrictionmodification genes has been made Wilson (Wi4).
Table m lists the sensitivities of over 20 Type II DNA
methyltransferases to m4C, nSC, hm5C, and m6A modification.
Most DNA methyltransferases are sensitive to non-canonical
modifications within their recognition sequences
(Bu5,MclO,Ne3,Po4), and this sensitivity may differ from that
of their restriction endonuclease partners.
Finally, several restriction endonuclease isoschizomers are
known to differ in their ability to cleave DNA which has been
methylated. Table IV lists over 20 known isoschizomer pairs
and one isomethylator pair, along with the modified recognition
sites at which they differ.
Effect of m5CG and m5CNG on restriction endonucleases
Enzymes that are not sensitive to site-specific methylation are
particularly useful for achieving complete digestion of methylated
DNA. For instance, endonucleases that are unaffected by mI5CG
and m5CNG are useful for digestion of plant DNA which is
frequently methylated at these positions. Endonucleases that are
unaffected by these two cytosine modifications include: Accll,
AflH, AhaIH, AseI, Asp700I AsuH, BbuI, BclI, BspHI, BspNI,
BstElI, BstNI, CviQI, DpnI, DraI, EcoRV, HinCll, HpaI, KpnI,
MboH, MseI, NdeI, NdeH, Pacd, RsaI, RspXI, SpeI, SphI, SspI,
Swal, TaqI, TthHBI and XmnI.
CpG sequences occur infrequently and are often methylated
in mammalian genomes (Mc9). Almost all the enzymes that could
generate large fragments of mammalian DNA are blocked by
this m5CpG modification at overlapping sites, including AatII,
ApeI, AvilI, BbeI, BmaDI, BssHll, BspMU, BstBI, ClaI, CspI,
Csp45I, EagI, EclXI, Eco47HI, FseI, FspI, Kpn2I MluI,
Mlu9273I, Mlu9273H, MroI, NaeI, NarI, NotI, NruI, Pfid, PmlI,
PpuAI, PvuI, RsrH, Sall, SaIDI, Sbol3I, SfiI, SmaI, SnaBI, Spll,
SpoI, XhoI and Xorfl (see Table I).
Only four enzymes suitable for pulsed field mapping of
eukaryotic chromosomes are known to cut msCG-modified
DNA: AcclI, AsuH, Cft9I and XinaI. It has been determined
that SfiI is sensitive to n5C modification at the second cytosine
of its recognition sequence, GGCm5CN5GGCC. SfiI is therefore
*
To whom correspondence should be addressed
sensitive
to
overlapping
m5CG
methylation
at
GGC"5CGN4GGCC sites in mammals and overlapping dcm
methylation at GGC'5CWGGNNGGCC sequences in E. coli..
m4C and "n5C Cytosine modifications
In some cases, a restriction enzyme may differ with to sensitivity
to m4C and m5C at a particular sequence. For example, BstNI
and MvaI cut I15C, but not m4C modified CCWGG sequences.
KpnI cuts GGTACm5C but not GGTACm4C. BstYI cuts RGATm5CY but not RGATm4CY. Restriction enzymes we have
tested for sensitivity to m4C include: AatI, Afll, AlwI, AvaII,
BanI, BglI, BstI, BstNI, BstYI, DpnI, FokI, MboI, MvaI, NarI,
Ncil, PflMI, Sau3A, and ScrFI.
Rate of cleavage at methylated restriction sites
m4C, m5C, hm5C, and m6A are bulky alkyl substitutions in the
major groove of B-form DNA. It is therefore not surprising that
site-specific DNA methylation can interfere with many sequencespecific DNA binding proteins (e.g. St2,Wa8) including binding
of restriction endonucleases and DNA methyltransferases. DNA
methylation may cause long-range perturbations of DNA minor
and major grooves, and a range of rate effects are observed when
modified substrates are used in restriction-modification reactions.
Results can be summarized as follows.
(1) Canonical site-specific methylation always inhibits DNA
cleavage by a restriction endonuclease. For example, M.BamHI
methylase modifies GGATm4CC; and BamHI endonuclease
cannot cut this methylated sequence.
(2) In about one half of the cases tested, methylation at noncanonical sites inhibits the rate of duplex DNA cleavage at least
ten-fold (Table I). However, in other cases non-canonical
methylation has no effect on restriction cleavage. For example,
BamHI cuts DNA which has been modified at GGATCm4C or
GGATCm5C, but cannot cut DNA methylated at GGATm5CC.
(3) There are a few examples in which non-canonical
methylation slows the rate of cleavage or permits nicking of one
strand of a hemi-methylated duplex. Examples of such rate effects
are presented in footnotes to Table I.
(4) Sometimes base modifications which lie outside a
recognition sequence can influence the rate of DNA cleavage by
a restriction enzyme. For example, NarI does not cut at
overlapping M.MvaI-NarI GGCGCCO4CCWGG sites (Nel);
and HaeIII cannot cut certain GGCCmT sites, where mT are
modifed thymine residues (Wil). Such methylation-induced
'action at
a
distance' may be
more common
than has been
2046 Nucleic Acids Research, Vol. 19, Supplement
previously appreciated. We have tested only a few enzymes for
sensitivity to base modifications outside their canonical
recognition sequences.
Effect of site-specific methylation on DNA methyltransferases
Twenty-three Type II methyltransferases have been tested for
sensitivity to non-canonical DNA modifications, of which nine
were blocked (MclO and Table IE). As with restriction
endonucleases, rate effects are sometimes seen with DNA
methyltransferases at non-canonically modified sequences. For
example, E. coli Dam methyltransferase is unaffected by GAT1mC, but methylates GATn'C relatively slowly. Such data is
summarized in Table II1 and footnotes to Table I.
Methylase/endonuclease combinations can produce novel
DNA cleavage specificities
Several strategies involving combinations of modification
methyltransferases and restriction endonucleases have been used
to generate rare or novel DNA cleavage sites.
For example, certain adenine methyltransferases may be used
in conjunction with the methylation-dependent restriction
endonuclease DpnI to create cleavages at eight- to twelve-basepair sequences (Mc6,Mcl2). M ClaI and DpnI have been used
to cut the 2.8 million base pair Staphylococcus aureus genome
into two pieces at the sequence ATCGATCGAT (Wel). Twelvebase-pair TCTAGATCTAGA M XbaI/DpnI sites in a
transposon have been introduced into bacterial genomes and
permit cleavage one or more times depending on the number of
transposons integrated (HaS).
Protection of a subset of restriction endonuclease cleavage sites
by methylation at overlapping methyltransferase/endonuclease
targets has been described (Hul ,Kll1,Ne6). This two-step 'crossprotection' strategy has produced over 60 new cleavage
specificities, and many more are possible (Ja2,Ka2,Kll,Ne6).
Extremely specific DNA cleavages may result from certain
'cross-protections.' For example, M-FnuDHINotI cleavage has
been used to cut the 4.7 million base pair E. coli K12 genome
into fourteen pieces (Qi2).
Methylases have been used to compete with endonucleases for
recognition sites in a method called methylase-limited partial
digestion. This method is particularly useful for performing partial
digests in agarose plugs for pulsed field gel electrophoresis
(Ha6). Blocking a subset of DNA methyltransferase sites by
overlapping methylation (sequential double-methylation) can
expose a subset of restriction endonuclease sites for cleavage
(Mc9,Ne3,Po3). For instance, M HpaH, M BamHI, and BamHI
have been used in a sequential three-step methyltransferase/methyltransferase/endonuclease reaction to achieve
selective DNA cleavage at the ten base pair sequence, CCGGATCCGG (McIO).
Polypyrimidine oligonucleotides have been used in DNA
triplexes to selectively mask restriction-modification sites. For
example, polyppyrimidine triplexes which overlap M. TaqI sites
have been used to enable selective restriction cleavage (Ma7).
Finally, methods based on the sequential use of purified lac
repressor protein, DNA methyltransferases, and restriction
endonucleases have been used to achieve highly selective DNA
cleavages (Ko2).
target sequences: mrr (m6A), mcrA (m5CG), mcr B (Rm5C)
(Br5,Dil,He3,Ral,Ra2). In vivo or in vitro modified DNA is
inefficiently cloned into E. coli. For example, human DNA which
is extensively methylated at "5CpG is restricted by mcrA (Wo2).
Appropriate non-restricting strains of E. coli (Go2,Krl, Ral,Ra2)
should be chosen for efficient transformation and cloning of
methylated DNA. Other species have such restriction systems
(e.g. Ma2).
Engineered altered methylase specificities
Many methylase gene have now been sequenced. Extensive
homologies between closely related enzymes (Wi3) or common
motifs (Po5,Sm3) allow new specificities to be developed (e.g.
Ba4,Tr4).
Data in electronic form
This paper is available as a text file on a 3.5' Macintosh diskette.
The data can be supplied as a Microsoft Word, Macwrite or MSDOS file. Please contact Michael McClelland at CIBR, phone
619 535 5486, FAX 619 535 5472. There are tentative plans
to provide the supplement issue on a CD-ROM.
ACKNOWLEDGEMENTS
This work is supported by grants from the National Institutes
of Health and the U.S. Dept. of Energy. We gratefully
acknowledge the editorial assistance of Charlie Peterson, Mike
Biros and Dotty Crosei.
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Kaplan D.A. and Nierlich D.P.: J. Biol. Chem. 250 (1975) 2395-2397.
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KaS. Karreman C. and de Waard A.: J. Bacteriol. 170 (1988) 2527-2532.
Ka6. Karreman C. and de Waard A.: J. Bacteriol. 170 (1988) 2533-2536.
Ka7. Karreman C., Tandeau de Marsac N. and de Waard A.: Nucleic Acids
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Ka8. Karreman C. and de Waard A.: J. Bact. 172 (1989) 266-272
Ka9. Karyagina A.S., Lunin V.G. and Nikolskaya I.I.: Gene 87 (1990)
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KalO. K4szubska W., Aiken C.R. and Gumport R.I.: Gene 74 (1988) 83-84.
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La4.
Lacks S.A., Mannarelli B.M., Springhorn S.S. and Greenberg B.: Cell
46 (1986) 993-1000.
LaS. Lacks S.A. and Springhorn S.S.: J. Bacteriol. 157 (1984) 934-936.
La6. Landry D., Looney M.C., Feehery G.R., Slatko B.E., Jack W.E. and
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La7. Landry D.: (unpublished observations).
La8. Lange C., Noyer-Weidner M, Trautner T.A., Weinewr M., and Zahler
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La9. Larimer F.W.: Nucleic Acids Res. 15 (1987) 9087.
LalO. Lautenberger J.A., Kan N.C., Lackey D., Linn S., Edgell M.H. and
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Lal 1. Lautenberger J.A. and Linn S.: J. Biol. Chem. 247 (1972) 6176-6182.
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Le2. Levy W.P. and Welker N.E.: Biochemistry 20 (1981) 1120-1127.
Lol. Lodwick D., Ross H.N.M., Harris J.E., Almond J.W. and Grant W.D.:
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Lul. Lui A.C.P., McBridge B.C., Vovis G.F. and Smith M.: Nucleic Acids
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Lu2. Lunnen K.D., Barsomian J.M., Camp R.R., Card C.O., Chen S.Z.,
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Lu4. Lunnen K.D., Morgan R.D., Timan C.J., Krzycki J.A., Reeve J.N.
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Lyl. Lynn S.P., Cohen L.K., Gardner J.F. and Kaplan S.: J. Bacteriol. 138
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Mal.
Ma2.
Ma3.
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Ke2.
Ke3.
Ku2.
Keshet E. and Cedar H.: Nucleic Acids Res. 11 (1983) 3571-3580.
Kessler C. and Holtke H-J.: Gene 33 (1985) 1-102.
Kim E.L. and Maliuta S.S.: FEBS Lett. 255 (1989) 361-364.
Kiss A. and Baldauf F.: Gene 21 (1983) 111-119.
Kiss A., Posfai G., Keller C.C., Venetianer P. and Roberts R.J.: Nucleic
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Kita K., Nobutsugu H., Oshima A., Kadonishi S. and Obayashi A:
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Koncz C., Kiss A. and Venetianer P.: Eur. J. Biochem. 89 (1978)
523 -529.
Koob M., Grimes E., and Szybalski W.: Science 241 (1988) 1084- 1086.
Korch C. and Hagblom P.: Eur. J. Biochem. 161 (1986) 519-524.
Korch C., Hagblom P. and Normark S.: J. Bacteriol. 161 (1985)
1236-1237.
Korch C., Hagblom P. and Normark S.: J. Bacteriol. 155 (1983)
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Kosykh V.G., Glinskaite I., Bur'yanov Ya.l. and Bayev A.A.: Doki.
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La2.
Labbe S., Xia Y. and Roy P.H.: Nucleic Acids Res.16 (1988) 7184.
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Kil.
Ki2.
Ki3.
Ki4.
Kll.
K13.
Kol.
Ko2.
Ko3.
Ko4.
Ko5.
Ko6.
Ko7.
Ko8.
Krl.
Kr2.
Ku3.
Kul.
33.
101-110.
La3.
Ma4.
MaS.
Ma6.
Ma7.
Ma8.
Ma9.
MalO.
Mcl.
Mc3.
Mc2.
Mc4.
McS.
Mc6.
Mc7.
Mc8.
Mc9.
MclO.
Mc 1.
McI2.
Mc13.
Mel.
Miu.
Mi2.
Mol.
Mo2.
Mo3.
Mul.
Myl.
Nal.
Na2.
Na3.
Macdonald P.M. and Mosig G.: EMBO J. 3 (1984) 2863-2871.
MacNeil D.J.: J. Bact. 170 (1988) 5607-5612.
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Mann M.B., Rao R.N. and Smith H.O.: Gene 3 (1978) 97-112.
Mann M.B. and Smith H.O.: Nucleic Acids Res. 4 (1977) 4211 -4221.
Mannarelli B.M., Balganesh T.S., Greenberg B., Springhorn S.S. and
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Maher L.J., Wold B., and Dervan P.B.: Science 245 (1989) 725-730.
Matvienko N.I., Kramarov V.M. and Irismetov A.A.: Bioorg. Khim.
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May M.S. and Hattman S.: J. Bacteriol. 122 (1975) 129-138.
McClelland M.: (unpublished results).
McClelland M.: Nucleic Acids Res. 9 (1981) 6795-6804.
McClelland M.: Nucleic Acids Res. 9 (1981) 5859-5866.
McClelland M.: J. Mol. Evol. 19 (1983) 346-354.
McClelland M.: Nucleic Acids Res. 10 (1983) rl69-r173.
McClelland M., Kessler L. and Bittner M.: Proc. Natl. Acad. Sci. USA
81 (1984) 983-987.
McClelland M., and Nelson M.: (unpublished results).
McClelland M. and Nelson M.: Nucleic Acids Res. 13 (1985)
r201 -r207.
McClelland M. and Nelson M.: Gene Amplification and Analysis,Vol.
5 (1987) J. Chirikjian, Ed., Elsevier, NY, pp257-282.
McClelland M. and Nelson M.: Gene 74 (1988) 169-176.
McClelland M. and Nelson M.: Gene 74 (1988) 291-304.
McClelland M., Nelson M. and Cantor C.R.: Nucleic Acids Res. 13
(1985) 7171-7182.
McClelland M. and Patel Y.: (unpublished observations).
Meda M.M. and Perler F.B.: (unpublished).
Miner Z. and Hattman S.: J.Bacteriol. 170 (1988) 5177-5184
Miner Z., Schlagman S.L. and Hatnman S.: Nucleic Acids Res. 17 (1989)
8149-8158.
Modrich P.: Quart. Rev. Biophys. 12 (1979) 315-369.
Molloy P.L. and Watt F.: Nucleic Acids Res. 16 (1988) 2335.
Morgan R.: (unpublished observations).
Mural R.J.: Nucleic Acids Res 15 (1987) 9085.
Myers P.A. and Roberts R.J.: (unpublished results).
Nagaraja V., Shepherd J.C.W., Pripfl T. and Bickle T.A.: J. Mol. Biol.
182 (1985) 579-587.
Nagaraja V., Shepherd J.C.W. and Bickle T.A.: Nature 316(1985)
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Nardone G.G. and Chirikjian J.G.: J. Biol. Chem. (1984) 10357-10362.
Nucleic Acids Research, Vol. 19, Supplement 2049
Na4.
Narva K.E., Wendell D.L., Skrdla M.P. and Van Etten J.L.: Nucleic
Acids Res. 15 (1987) 9807-9823.
NaS. Nathans D. and Smith H.O.: Ann. Rev. Biochem. 44 (1974) 273-293.
Nel. Nelson M: (unpublished results).
Ne2. Nelson M., Christ C. and Schildkraut I.: Nucleic Acids Res. 12 (1984)
5165-5173.
Ne3. Nelson M. and McClelland M.: Nucleic Acids Res. 15 (1987)
r219-r230.
Ne4. Nelson M. and McClelland M.: Nucleic Acids Res. 17 (1987) r398-415.
NeS. Nelson M. and McClelland M.: (unpublished observations).
Ne6. Nelson M. and Schildkraut I.: Methods in Enzymology 155 (1987)
31-48.
Ne7. Nelson J.M., Miceli S.M., Lechevalier M.P. and Roberts R.J.: Nucleic
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Mol. Genet. Mikrobiol. i Virusol. 12 (1983) 5-10.
Ni2
Nikolskaya I.I., Lopatina N.G., Antikeicheva N.V. and Debov S.S.:
Nucleic Acids Res. 7 (1979) 517-528.
Ni3. Nikolskaya I.I., Lopatina N.G., Suchkov S.V., Kartashova I.M. and
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Ni4. Nikolskaya I.I., Lopatine N.G., Sharkova E.V., Suchkov S.V., Somodi
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Nol. Noyer-Weidner M., Jentsch S., Kupsch J., Bergbauer M. and Trautner
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No2. Noyer-Weidner M., Jentsch S., Pawlek B., Gunthert U. and Trautner
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No3. Noyer-Weidner M., Pawlek B., Jentsch S., Gunthert U. and Trautner
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Nul. Nur I., Szyf M., Razin A., Glaser G., Rottem S. and Razin S.J.:
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Nwl. Nwankwo D.O. and Wilson G.G.: Mol. Gen. Genet. 209 (1987)
570-574.
Nw2. Nwankwo D.O. and Wilson G.G.: Gene 64 (1988) 1-8.
Onl. Ono A . and Ueda T.: Nucleic Acids Res. 15 (1987) 219-231.
Pal. Patel Y., Schildkraut I. and McClelland M.: (unpublished observations).
Pa2. Patel Y., Nelson M. and McClelland M.: (unpublished observations).
Pel. Pech M., Streeck R.E. and Zachau H.G.: Cell 18 (1979) 883-893.
Pe2. Petrosyte M. and Janulaitis A.: Bioorg. Khim. 7 (1981) 1885- 1887.
Pil. Piekarowicz A. and Goguen J.D.: Eur. J. Biochem. 154 (1986) 295-298.
Pi2. Piekarowicz A. and Stein D.C.: (personal communication).
Pi3.
Piekarowicz A., Yuan R. and Stein D.C.: Nucleic Acids Res. 16 (1988)
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Pi4. Piekarowicz A., Yuan R. and Stein D.C.: Nucleic Acids Res. 16 (1988)
9868.
PiS. Piekarowicz A., Yuan R. and Stein D.C.: Nucleic Acids Res. 17 (1989)
10132.
Pi6.
Pirrotta V.: Nucleic Acids Res. 3 (1976) 1747-1760.
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Po3. Posfai, G. and Szybalski W.: Nucleic Acids. Res. 16 (1988) 6245.
Po4. Posfai G. and Szybalski W.: Gene 74 (1988) 179-181.
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Po6. Povilonis P., Vaisvila R., Lubys A. and Janulaitis A.: (personal
Prl.
Pr2.
Pr3.
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Prere M.F. and Fayet O.: Ann. Inst. Pasteur Microbiol. 136A (1985)
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Price C., Shepherd J.C.W. and Bickle T.A.: EMBO J. 6 (1987)
1493-1497.
Qiang B-Q.: (personal communication).
Qiang B-Q. and Nelson M.: (personal communication).
Qiang B-Q., McClelland M., Poddar S., Spokauskas A. and Nelson M.
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Qul. Quint A. and Cedar H.: Nucleic Acids Res. 9 (1981) 633-646.
Ral. Raleigh E.A., Murray N.E., Revel H., Blumenthal R.M., Westaway
Qil.
Qi2.
Qi3.
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Ra2.
Ra3.
Rel.
Re2.
Re3.
Re4.
Ril.
Ri2.
Rol.
Ro2.
Ro3.
Ro4.
RoS.
Ro6.
Ro7.
Rul.
Sal.
Sa2.
Sa3.
Scl.
Sc2.
Sc3.
Sc4.
ScS.
Raleigh E.A. and Wilson G.: Proc. Natl. Acad. Sci. USA 83 (1986)
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Razin A., Urieli S., Pollack Y., Gruenbaum Y. and Glaser G.: Nucleic
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Rees P.A. and Brenner J.S.: (unpublished).
Rees P., Nwankwo D.O., Wilson G.G. and J. Benner J.S.: Gene 74
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Renbaum P., Abrahamove D., Fainsod A. and Wilson G.G.: Nucleic
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Revel H.R. and Georgeopoulos C.P.: Virology 39 (1969) 1-17.
Ritchot N. and Roy P.H.: Gene 86 (1990) 103-106.
Richards D.F., Linnett P.E., Oultram J.D., and Young M.: J. Gen.
Micro. 134 (1988) 3151-3157.
Roberts R.J.: (unpublished results).
Roberts R.J.: Nucleic Acids Res. 11 (1983) rl35-rl67.
Roberts R.J.: Nucleic Acids Res. 16 (1988) r271-r313.
Rodicio M. and Chater K.F: Gene 74 (1988) 39-42.
Rodicio M. and Chater K.F: Mol. Gen. Genet. 213 (1988) 346-353.
Roy P.H. and Smith H.O.: J. Mol. Biol. 81 (1973) 427-444.
Roy P.H. and Smith H.O.: J. Mol. Biol. 81 (1973) 445-459.
Rubin R.A. and Modrich P.J.: J. Biol. Chem. 252 (1977) 7265-7272.
Sain B. and Murray N.E.: Mol. Gen. Genet. 180 (1980) 35-46.
Sano H. and Sager R.: Eur J. Biochem. 105 (1980) 471-480.
Sato S., Nakazawa K. and Shinomiya T.: J. Biochem. 88 (1980)
737-747.
Schertzer E., Auer B. and Schweiger M.: J. Biol. Chem. 262 (1987)
15225-15231.
Schildkraut I., Morgan R. and Looney M.E.: (unpublished results).
Schlagman S.L., Miner Z., Feher Z. and Hattman S.: Gene 73 (1988)
517-530.
Schlagman S.L. and Hattman S.: Gene 22 (1983) 139-156.
Schlagman S.L. and Hattman S.: Nucleic Acids Res. 17 (1989)
9101-9112.
Sc6.
Sc7.
Sc8.
Sc9.
Sc1O.
Scd 1.
Schlagman S., Hattman S., May M.S. and Berger L.: J. Bacteriol. 126
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Schneider-Scherzer E., Auer B., De Groot E.J. and Schweiger M.: J.
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Schnetz K. and Rak B.: Nucleic Acids Res. 16 (1988) 1623.
Schoner B., Kelly S. and Smith H.O.: Gene 24 (1983) 227-236.
Schoenfeld T., and Leland D.: (pers. comm.).
Schoenfeld T., Mead D.A., and Fiandt M.: Nucleic acids Res. 17 (1989)
4417.
Sc12.
Sel.
Se2.
Shl.
Sh2.
Sh3.
Sil.
Skl.
Sll.
S12.
S13.
Sml.
Sm2.
Sm3.
Sol.
So2.
So3.
Sti.
St2.
St3.
St4.
StS.
Sciaky D. and Roberts R.J.: (unpublished results).
Seeber S., Kessler C. and Gotz F.: Gene 94 (1990) 37-43.
Selker E.U., Cambareri E.B., Garrett P.W., Haack K.R., Jensen B.C.
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Shibata T., Ikawa S. and Ando T.: Microbiology-1982, D. Schlessinger,
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Shimizu-Kadota M. and Shibahara-Sone H.: Agric. Biol. Chem. 53 (1989)
2841-2842.
Shields S.L., Burbank D.E., Grabherrr R. and Van Etten J.L.: Virology
176 (1990) 16-24
Silber K., Polisson C., Rees P., and Benner J.S.: Gene 74 (1988) 43-44.
Skrzypek E. and Piekarowicz A.: (unpublished).
Sladek T.L., Nowak J.A. and Maniloff J.: J. Bacteriol. 165 (1986)
219-225.
Slatko B.E., Benner J.S., Jager-Quinton T., Moran L.S., Simcox T.G.,
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9781-9796.
Slatko B.E., Croft R., Moran L. and Wilson G.G.: Gene (1988) 45-50.
Smith H.O.: Science 205 (1979) 455-462.
Smith H.O. and Nathans D.: J. Mol. Biol. 81 (1973) 419-423.
Smith H.O., Annau T.M. and Chandrasegaran S.: Proc. Natl. Acad.
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Som S., Bhagwat A.S. and Friedman S.: Nucleic Acids Res. 15 (1987)
313-332.
Sohail A., Bhagwat A.S. and Roberts R.J.: (unpublished).
Song Y-H., Rueter T. and Geiger R.: Nucleic Acids Res. 16 (1988) 2718.
Stefan C., Xia Y., and Van Etten J.L.: Nucleic Acids Res. (1991) (in
press).
Stemnberg N.: J. Bacteriol. 164 (1985) 490-493.
Streeck R.E.: Gene 12 (1980) 267-275.
Striebel H.M., Schmnitz G.G., Kaluza K., Jarsch M. and Kessler C.:
Gene 91 (1990) 95-100.
Strobl J.S. and Gaido M.: (unpublished results).
2050 Nucleic Acids Research, Vol. 19, Supplement
St6.
St7.
Sul.
Su2.
Su3.
Su4.
Szl.
Sz2.
Sz3.
Sz4.
Tal.
Strobl
J.S. and Thompson E.B.: Nucleic Acids Res. 12 (1984)
8073-8084.
Sturm R.A. and Yaciuk P.: Nucleic Acids Res. 17 (1989) 3615.
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Tautz N., Kaluza G., Lane F., Frey B., Schmitz G., Jarsch M.,
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Theriault G. and Roy P.H.: Gene 19 (1982) 355-359.
Th2.
Theriault G., Roy P.H., Howard K.A., Benner J.S., Brooks J.E., Waters
Ta3.
A.F. and
Trl.
Tr2.
Tr3.
Tr4.
Url.
Val.
Va2.
Va3.
Va4.
Va5.
Va6.
Vel.
Vii.
Wa3.
Wa4.
WaS.
Wa6.
Nucleic Acids Res. 13 (1985) 8441-8461.
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Trautner T.A.: Current Topics Microbiol. Immunol. 108 (1984) 11-22.
Trautner T.A., Pawlek B., Gunthert U., Canosi U., Jentsch S. and Freund
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Trautner T.A., Balganesh T.S., and Pawlek B.: Nucleic Acids Res. 16
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Urieli-Shoval S., Gruenbaum Y. and Razin A.: J. Bacteriol. 153 (1983)
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Van Cott E.M. and Wilson G.G.: Gene 74 (1988) 55-59.
Van Cott E.M. and Wilson G.G.: (unpublished).
Van der Ploeg L.H.T. and Flavell R.A.: Cell 19 (1980) 947-958.
Van Etten J.L.: (personal communication).
Vanyushin B.F. and Dobritsa A.P.: Biochim. Biophys. Acta 407 (1975)
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Vasquez C. and Vicuna R.: Arch. Biol. Med. Exp. 15 (1982) 417-421.
Venetianer P. and Kiss A.: Gene
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Vinogradova M.N., Gomova E.S., Uporova T.M., Nikolskaya I.I.,
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Akad. Nauk. SSSR 295 (1987)
Amplification
Doklady
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Walder R.Y., Walder J.A. and Donelson J.E.: J. Biol. Chem. 259 (1984)
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Wa7.
Wa8.
Wel.
We2.
Whl.
Wh2.
Walter.
J., Noyer-Weidner M. and Trautner T.A. EMBO J.
(1990)
1007-1014.
Wang R.Y.H., Zhang X-Y.,
Khan
R., Zhou Y., Huang L-H. and Ehrlich
M.: Nucleic Acids Res. 14 (1987) 9843-9860.
Weil M.D. and McClelland M.: Proc. Natl. Acad. Sci. USA 86 (1989)
51-55.
Weil M.D., Nelson M. and McClelland M.: (unpublished)
Whitehead P.R. and Brown N.L.: FEBS Lett. 155 (1983) 97-101.
Whitehead P.R. and Brown N.L.: J. Gen.
Microbiol. 131 (1985)
951-958.
Wh3.
Whitehead
P., Jacobs D. and Brown N.L.: Nucleic Acids Res. 14 (1986)
7031-7045.
Wil.
Wi2.
Wi3.
Wiatr C.L. and Witmer H.J.:
Wigler M., Levy
Wilke
K., Rauhut
Behrens B. and
Wi4.
Wilson
Xi2.
Xi3.
Xi4.
XiS.
Xi6.
Xul.
Yol.
Yo2.
Yo3.
Yo4.
Gingeras T.R.:
732-736.
Vol.
Wal.
Wa2.
Wul.
Xil.
329-334.
Sullivan K.M. and Saunders J.R.: Nucleic Acids Res. 16 (1988)
4369-87.
Sullivan K.M. Saunders J.R.: Mol. Gen. Genet. 216 (1989) 380-387.
Szilak L., Venetianer P. and Kiss A.: Nucleic Acids Res. (1990)
4659-4664.
Sznyter L.A. and Brooks J.E.: Gene 74 (1988) 53.
Sznyter L.A., Slatko B., Moran L., O'Donnell K.H. and Brooks J.E.:
Nucleic Acids Res. 15 (1987) 8249-8266.
Szomolanyi E., Kiss A. and Venetianer P.: Gene 10 (1980) 219-225.
Tasseron-de Jong J.G., Aker J. and Giphart-Gassler M.: Gene 74 (1988)
147-149.
Ta2.
Wol.
Wo2.
G.G.:
J. Virol. 52
(1984) 47-54.
(1981) 33-40.
E., Noyer-Weidner M., Lauster R., Pawlek B.,
D. and Perucho M.: Cell 24
Trautner T.A.: EMBO
Gene
74
(1988)
281-289.
J. 7
(1988) 2601-2609.
Yo5.
Yo6.
Zal.
Zil.
Wong K.K. and McClelland M.: Nucleic Acids Res. 19 (1991) (in press).
Woodcock D.M., Crowther P.J., Diver W.P., Graham M., Batemen
C., Baker D.J. and Smith S.S.: Nucleic Acids Res. 16 (1988)
4465-4482.
Wu J.C. and Santi D.V.: Nucleic Acids Res. 16 (1988) 703-717.
Xia Y., Burbank D.E., Uher L., Rabussay D. and Van Etten J.L.: Mol.
Cell. Biol. 6 (1986) 1430-1439.
Xia Y., Burbank D.E., Uher L., Rabussay D. and Van Etten J.L.:
Nucleic Acids Res. 15 (1987) 6075-6090.
Xia Y., Burbank D.E. and Van Etten J.L.: Nucleic Acids Res. 14 (1986)
6017-6030.
Xia Y., Morgan R., Schildkraut I. and Van Etten J.L.: Nucleic Acids
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Xia Y., Narva K.E. and Van Etten J.L.: Nucleic Acids Res. 15 (1987)
10063.
Xia Y. and Van Etten J.L.: Mol. Cell Biol. 6 (1986) 1440-1445.
Xu G., Kapfer W., Walter J. and Trautner T.A.: (unpublished).
Yolov A.A., Vinogradova M.N., Gromova E.S., Rosenthal A., Cech
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Yoo O.J. and Agarwal K.L.: J. Biol. Chem. 255 (1980) 6445-6449.
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Youssoufian H. and Mulder C.: J. Mol. Biol. 150 (1981) 133-136.
Zacharias W., Larson J.E., Kilpatrick M.W. and Wells R.D.: Nucleic
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Zieger M., Patillon M., Roizes G., Lerouge T., Dupret D. and Jeltsch
J.M.: Nucleic Acids Res. 15 (1987) 3919.
TABLE I: Methylation sensitivity of restriction
Restriction Recogniton
enzyme sequence
CCWGG
AacI
AGGCCT
Aa-d
Aatill
Sites
cut
Nucleic Acids Research, Vol. 19, Supplement 2051
endonucleases a
Sites not
References
cut
%0"16
Cm5CWGG
AGGmSCCT
Br8
Nel
AGGCm5CT
So3
AGGCm4CT
Nel
Nel
Fol
Lu2,Mc3
GACGTTm5C
GACGTC
GAm5CGTC
A~I&
GTMKAC
GTMKm6AC#
GTMKAm5C
AccIl
CGCG
TCCGGA
mSCGCG
Tm5CCGGA
Ga2
Ke3,La2,Sc2
TCCGGm6A
TCmSCGGA
AflI
GGWCC
Mc 1,Wh2
GGWCm5C??
GGWCm4C
AflH
ClTAAG
I?
m5CTrAAG
Nel
CIT-Am6AG
Ahall
ACRYGT
GRCGyC b
Nel
Ka2,Hul
Am5CRYGT
GRm5CGYC
GRCGYm5C
AM
Gr4,Mc 1 1 ,Ne2
m6AGCI
AGCT
AGm4CT
Hul,Wol
Bu5
Ne4
AGm5CT#
AlwI
AGhm5CT
GGm6ATC
GGATC
GGATm4C
AmaI
Aosll
AaI
AxI
,paLI
AguI
AseI
Asg7OOI
TCGCGA
GRCGYC
GGGCCC
ACGCGT
GTGCAC
CCWGG
CYCGRG
ATTAAT
GAAN4TTC
As1718I GGTACC
GRm5CGYC
GGGm5CCC#
GTGCm6AC
GGGCCm5C
Am5CGCGT
GTGCAm5C
Cm5CWGGQ,b
m5CCWGG
ATpn6AAT
GAm6AN4TTC
Gm6AAN4TTC
AvaI
TTCGAA
TGATCA
CYCGRG
Nel,Qi2
Fol ,Hol,Ho2
K11,Mcl 1 ,Ra3
Ka7,Ka8
Nel
Nel
m5CYCGRG#
GAAN4TPm5C
GGTm6Am5CC b
YfmSCGAA
Cm5CCGGG
Mul,Ne4
GGTACm5C
GGTAm5Cm5C
AsuIl
Ata
Mc13
Eh2,Gr4,Va3
La9,Tr2
TCGCGm6A
TGm6ATCA
m5CYCGRG
CYm5CGRG
CTCGm6AG b
b
Nel
Ro3,Scl2
Eh2,Nel
Ka4,Ka7,Mcl 1
Ne2
2052 Nucleic Acids Research, Vol. 19,
Restriction Recognition
sequence
GGWCC
enzme
Aal
Supplement
Sites
cut
GGWCm4C b
Sites not
cut
References
GGWm5CC
Ba3,Ko3
MclO,Mcl 1
Hul
Nel
Gil,Tr2
GGWCm5C
GGWhmSChmSC
A3I
BaII
AGCGCT
famHl
GGATCC
m6AGCGC
TGGCCA
GGATCm5C
GGm6ATCC
GGm6ATCm5C
AGm5CGCT
TGGm5CCA#
TGGCm5CA b
GGATmCc#
Br8,Drl,Hal,Hul
La7
GGATm5CC
GGAltm5Chm5C
GGATCm4C
BpujF1 GGATCC
IamK[ GGATCC
GGYRCC b
BanI
aII
BIOI
Bj2eI
BiHI
BbrPI
BbKI
BbvI
BclI
BcnI
BZI
GRGCYC
ATCGAT
GGCGCC
GGm6ATCC
GGm6ATCC
GGm5CGCC
GGYRCm4C
GRGCYm5C
GGATm4CC
GGATm4CC
Co3,Ka2
GRGm5CYC
ATCGm6AT
GGCGm5CC
Anl,Shl
Anl,Shl
GGm5CGCC
Fol,Ne2,Ne6
Sul
Co3,Ne2,Sh2
GGCGCm5C
GRCGYC
CACGTG
GAAGAC
GCWGC
TGATCA b
CCSGG
CGCG
GRm5CGYC
m5CAm5CGTG
GAAGAm5C
Gm5CWGC#
TGATm5CA
m5CCSGG
TGm6ATCA
TGAThm5CA
Cm4CSGG#
m5CGCG
m5C11AAG
Co3
Wol
Fol
Dol,Hal,Va5
Bi4,Br8,Eh3,Ro3
Hul
Ja3.,Ja6,KlI
Ku2
Wol
DftI
B--II
CTTAAG
GCCN5GGC
GCm5CN5GGC b
Bjl
AGATCT b
AGm6ATCT
Gm5CCN5GGC Kll,Ko3,Mcl1,Ne2
GCCN5GGm5C b
GCm4CN5GGC b
AGATm5CT
Bi4,Br8,Drl,Dyl,Eh3
?
AGAPIm5cT
GGm6ATC
Hul,Pi6
Bol
CGATm6CG
GGWCm5C
Qi2
BinI
BmaDI
GGATC
CGATCG
Bfe2l6I GGWCC
BnaI
GGATCC
I-W
BaAI
BiOI
BsmI
BsmAI
106I
GGTCTC
YACGTR
GATN4ATC
GAATGC
GTCTC
ATCGAT
CGm6ATCG
GGm6ATCC
GAATGm5C
GGATm4CC
GGATm5CC#
GGTCPwrm5C
YAm5CGTR
GATN4AT5C
Ma9
Nel
Gm6AATGC
Fol
Fol
Fol
Fol,Nel
GTCTm5C
ATCGm5AT#
Fol
Ne5
Nucleic Acids Research, Vol. 19, Supplement 2053
Restriction Recognition
enzyme sequence
BS286I GDGCHC
BZHI TCATGA
Sites
cut
GDGCHm5C
Sites not
cut
GDGmSCHC
TCm6ATGA
TCATGm6A
SMlI
ACCTGC
TCCGGA
ACCTGm5C
SNI
CCWGG
m5CCWGG
TCCGGm6A
T'5CCGGA
References
Fol,Ne2,Ne6
Pa2
Mci
Fol
La2,Sc2
TCm5CGGA
Ne4
CmSCWGG
RWHII
tBHll
ATCGAT
TGATCA
GCGCGC b
GGATCC
LtBI
ATCGm6AT
T&m6ATCA
zil
zil
GmSCGCGC
Ne4,Qi3
Ne4
GGm6ATCC
GGATm4CC
GGATCmSC
'GGATm5CC
GGATCm4C
TfCGm6AA
TTCGAA
Trm5CGAA
BstEll
GGTNACC
BstEfI
BstGI
GATC b
TGATCA
CCWGG b
GGTNAm5Cm5C b
GGTNAhm5Chm5C
GGTNACm4C
m5CCWGG b
hmsChmsCWGG
Cm5CWGG
Cm4CWGG
m5CmSCWGG b
.-lUI
BstXI
BstYI
CGCG
CCAN6TGG
RGATCY
ciiI
CfoI
CTGCAG
CGCG
CCGG
CTCGAG
CCGG
GGCC
CTCGAG
GGGC
fr6I
YGGCCR
CAGCTG
BsuBI
BsuEI
BQlFI
RS-QI
DaRI
cft9I
CCCGGG b
Gm6ATC
TGm6ATCA
m5CGCG
RGm6ATCY
RGAT 5CY
Ne5
m5CCAN6TGG
Ne2
Ne4
Nel
CTGCm6AG#
Gal,Jel,St5,Shl
Gal ,Jel,St5,Shl
Je1
Jel
Je2
Gu6,Ki2,Ki3
Nel
Ehl
Hul
RGAP114CY
m5CGCG#
m5CCGG#
CTm5CGAG#
mCCGG
GGm5CC# b
CTCGm6AG
Gm5CGC
Ghm5CGhmsC
YGGm5CCR#
CmSCCGGG
CCm5CGGG
Nel
Ne4
Wol
Hu 1,Mc 11
Nel
Myl,Ro3
Ro3
Gr4,Hul,Mcl 1,Ro3
Nel
Kll
CAGm4CTG#
Bu5
CAGmSCTG
m4CCCGGG
Bu6
m5CCCGGG
Cm4CCGGG#
CCm4CGGG
2054 Nucleic Acids Research, Vol. 19, Supplement
Restriction Recognition
enzyme sequence
£iOI RCCGGY
f13I GGNCC
ATCGAT
Lia
TGATCA
CGGWCCG
Cz45I
CviBI
CviPI
£NAPI
TTCGAA
GATC
GATC
GANTC
RGCY
cc
Sites
cut
CGGWCm5CG
I?
I?
?
I?
?
cm5c
GTAC
CTNAG
DpnI
Gm6ATC b
Gm6ATC
Gm6ATm5C b
I?
EareI
agI
CGGCCG
EarI
GAAGAG
Bi5,K1
Bi5,Kli
Ca4,Mc 1l,Mc i2,Ne4
Woi
Mc3
Fil,Ro3
Mcii
ATCGm6AI*
TGm6ATCA
CGGWmSCCG
m5CGGWCCG
TTCGm6AA
Gm6ATC#
Gm6ATC
Gm6ANTC#
RGmSCY#
m5cc#
GTm6ACG
I?
Xii,Xi6
Xi3
Sh3,Xi2
Xi4
YGGm5CCR#
YGGCm5CR
CGGm5CCG
Mcii
GATC
GATm4C
GAT5C
Gm6ATc#
TITA6AA
I?
I?
Ne4,Scl 1
Ri2
Xi2,Xi5
Ho3,Ne2
Hul
La3,Mc 1i,Vol
Ne4
Ne5
Del,La3,La4,La5,Ma6,Vo1
Nel
Sc8
Ja2,Whl
m5CTNAG#
b"n5CTNAG
Gm6ATm4C
DraI
Rm5CCGGY#
GGNm5CC#
')6ATCGAT
DdI
GATC
TITAAA
RGGNCCY
YGGCCR
References
A1m5CGAT
GTAm5C
CviQI
Sites not
cut
RGGNCm5CY
m5CGGCm5CG
Gm6AAGAG
GAAGm6AG
Ne4
m5C-wpn5C 1p5C Nel
GGTANm6ACC
GGTAm6ACC#
Br2
CGGCCG
m5CGGCm5CG
Qi3
Eco47I GGWCC
m6AGCGCT
E&Q47M AGCGCT
GAGN7GTCA b
TGAN8TGCT b
Eg&B
&QDXXU TCAN7AATC b
GAGN7ATGC
F,&2E
AACN6GTGC b
F.gK
E&20109I RGGNCCY
AGAhm5CIh5C
F&2PI AGACC b
b
I&P15 CAGCAG
CGGm5CCG
GGWCm5C
AGm5CGCT
Gm6AGN7GmTCA# b
TGm6AN8mTGCT # b
TCAN7m6AAmTC # b
Gm6AGN7ATGC
Am6ACN6GmTGC# b
RGGNCm5CY
AGm6ACC#
Cm6AGCAG#
Ja5
Nel,Ne4
Bi2,Co6,Fu2
Bi2,LalO,Lal 1
Pil
Co6,Fu2
Bi2,Bi3,Kal
Sc8
Bal,Ba2,Ha2,Re4
Hu2
Nucleic Acids Research, Vol. 19, Supplement 2055
Restriction Recognition
enzyme sequence
GAAITC
EQQRI
EQRII
CCWGG
Sites
cut
Sites not
cut
References
GAATrhm5C
Gm6AATTC b
GAm6ATrrd
GAATPm5C b
Mci 1,Ne2,Rul
m5cCwGG b
m4CCWGG
Brl,Br8,Dul
Hul,Ka3,Tal
Ku3,Yol
FcoR124 GAAN6RTCG b
Cm4CWGG
Cm5CWGG#
CCm6AGG
hm5Chm5CWGG
Gm6ATATC#
GATm6ATC
GAm6AN6RTCG
GAAN6RmTCG
Bo5,Mcl 1
Bu3
Hul,Ka3
Mcl 1,Ne2,Wol
Fll
Pr2,Pr3
Bil
EcoRl24/3 GAAN7RTCG b
m6A
Prl,Pr2
GGCGCC
Gm5CTNAGC
Gm5CNGC
Co2
Ne4
Ko3,Tr2
GCNGm5C
m5CGCG
CGm5CG
Gal,Ga2,Ne2,Ne6,St6
FQRV
EheI
FnIuI
Fnu4lH
GATATC
GGCGCC
GCTNAGC
GCNGC
EnuDII
CGCG
EnEI
GATC
CATCC
FokI
GATATm5C b
GCTNAGm5C
Gm6ATC b
CATmSCC
CATCm5C b
GGm6ATG
Cm6ATCC
CATCm4C
GGCCGGCC
FspI
ki=ll
TGCGCA
RGCGCY b
HaelII
GGCC
HgI
agicI
H.CII
HgiEI
HgJm
lIhaI
GGCm5C
CCGG
GACGC
GRGCYC
GGYRCC
GGWCC
GGWCC
GGYRCC
GCGC
GRGCYm5C
Bu4,Na5,Ro3
Lul,Ne2
Po3,Po4,Sc2
Nel
GGm5CCGGm5CC Ne7
GGCm5CGGCC
GGm5CCGGCC
Ne4
TGm5CGCA
Eh2,Gr4,Ka2,Ko3,Mc 1i,Pi5
RGm5CGCY
RGhm5CGhm5CY Hul
Ba3,Ka2,Ko3,Ma5
GGm5CC# b
GGhm5Chm5C
Cm5CGG#
Hul
Eh2,Wal
GAm5CGC
Nel
GACGm5C
GRGm5CYC
GGYRCm5C
GGWCm5C
GGWCm5C
Mcii
GGYRCmSC
Gm5CGC#
GCGm5C
Ghm5CGhm5C
Fol,Ne2,Wh3
Erl
Erl
Erl
Wh3
Eh2,Ko3,Sml
Mcil,
Hul
20S6 Nucleic Acids Research, Vol. 19, Supplement
Restriction Recognition
enzyme sequence
GANTC
jIll
Sites
cut
HizcIll
GTYRAC
GTYRAm5C
Hindll
GTYRAC
GANTC
GANTm5C,b
Sites not
cut
References
Gm6ANTC#
GTYRm6AC
GTYRAwm5C
GTYRm6AC*
Ma5
Gr4,Ro7
Hul
Ro7
Gm6ANTC
Chl,Col,Ne2,Pel
GANVmSC
Hindf
AAGCIT
m6AAGC1T#
AAGm5CT
AAGhm5CT
HinPI
GCGC
GTTAAC
Gm5CGC
G1TAm6ACt
GUTAAm5C
G1TAAhm5C
HD-an
HDhI
KDn2I
m4CCGG
m5CCGG b
CCGG
Eh3,Mcl1,Ne2
GGTACm4C
Nel
Mcl,Nel
Nel
Nel
GATm4C
1m5CCGGA
TCm5CGGA
m5CCGCGG
Cm5CGCGG
Am5CGT b
Gm6ATN4m6ATC
Gm6ATC#
GATm5C b
GAThmSC
Mo2
St4
Br5,Gel,Mc8
Hul,Ro3
Tm5CTPm15C b
GAAGm6A#
Ba3,Mcl 1,Mcl2,Ne2
RGm6ATCY
Onl
TCACm5C
GGTACC b
GGTAm5CC
GGTACm5C
GGTAm5Cm5C b
TCCGGm6A
LrI
CCGCGG
MaeII
MamI
MboI
MboII
ACGT
GATN4ATC
GATC b
GAAGA
Br8,Gr4,Hul ,Yo3
Hul
Be3,Bu6,Eh2,Ma5
Ko3,Qul,Wa5
Cm4CGG b
Cm5CGG#
hm5Chm5CGG
PI5CACC#
GGTGm6A
GGTm6Am5CC
TCACC
TCCGGA
Hul
Br8,Gr4,Ro7
Ne2
Hul,Ka3
Mc 1,Ne6
Hul
Fol,Mcl 1,Ne2
Qi2
Gm6AAGA
mIm,
RGATCY b
RGATn4CY
ACGCGT
?2UI9273I TCGCGA
Mlu927311 GCCGGC
Lu~I
Mml
GATC
CCTC b
m6ACGCGT
RGATV5CY
Am5CGCGT
T'5CGCGA
Gm5CCGGC
GCm5CGGC
Gm6ATC
m5CCTC
m5Cm5CTml5C
Mcl 1,Shl,St5,Qi3
Nel
Nel
Bo4
Eh3,Mcll
Nucleic Acids Research, Vol. 19, Supplement 2057
Restriction Recognition
enzyme sequence
CCWGG b
MphI
TCCGGA
MI
Sites
cut
TCCGGm6A
Sites not
cut
Cm5CWGG
Pm5CCGGA
TCm5CGGA
MseI
MvaI
Ms-tll
TTAA
CCGG b
'1116AA
m4CCGG
Cm4CGG
Cm5CGG
CCTNAGG
CCWGG
m5CCGG#
hm5Chm5CGG
m5CCTNAGG
Cm5CWGG b
Cm4CWGG#
m5CCWGG
CCm6AGG b
m4CWGG b
msCm5CWGG b
MvnI
NI
CGCG
GCCGGC b
References
Ro3
Mcl,Nel
Nel
Nel
Eh2,Je2,Va3,Wal,Wa5
Bu6,Hul
Mcii
Bu4,Kul
Gr3,Ku3
m5CGCG
Nel
Nel
Gm5CCGGC
Eh3,K1i,Mc 1i,Ne5
GCm5CGGC
GCCGGm5C
NanlI
Gm6ATC b
Gm6ATC
GATC
Gm6ATm5C b
GATm5C
Ko3,Mc 1 l,Ne5
Nel
Br8,Ko3,Mc 1 1
Kll,Ne2,Ne4
Pal,Ne5
I
GGCGCC
GGCGCm5C
NciI
CCSGG
m5CCSGG
GGm5CGCC
GGCGCm4C
Cm4CSGG
CCATGG
CCm6ATGG
Cm5CSGG b
m4CCATGG b
Qil
GAAGm6A
Ng2BI
AGATCT
GAAGA
CATATG
GATC
TCACC
AGm6ATCT b
NgQPI
RGCGCY
RGm5CGCY
NgoIPl
GGCC
GGm5CC#
NheI
GCTAGC
CATG
GCTAGm5C
Cm6ATG#
Mci3
Be4,Mci 1
Mc9
Pi3,Pi4
Ko3 ,Ko5
Ko3,Ko5
Su3,Su4
Kli,Mc 1 ,Ne2
Lal,Mo3
GATC
GATC
Pal
Pal
GCGGm5CCGIC
GCGGCm5CG;C
Mcii
NcoI
m5CCATGG
NcrI
NcuI
NdeI
NdelI
m5CATATG b
m6A
GATm5C b
Gm6ATC
Tm5CACC
GGCm5Cb
mam
NmuDI
NmuEI
NotI
Gm6ATC b
Gm6ATC b
GCGGCCGC
NMI
TCGCGA
NsiI
ATGCAT
Gm6ATC
Gm6ATC
GCGGCCGm5C
TCGm5CGA
Tm5CGCGA
St5,Qi2
Nel,Qi3
TCGCGm6A
Ne2
ATGCm6AT
Be5
Woi
ATGm5CAT
2058 Nucleic Acids Research, Vol. 19, Supplement
Restriction Recogniton
enyme sequence
NBII CMGCKG
alM[
CCAN5TGG
PfI
GATC
CGTACG
CTCGAG
nR7I
P;LAI
Sites not
cut
Cm5CGCKG
Cm4CAN5TGG
CmSCAN5TGG
Gm6ATC
CGTAm5CG
CTCGm6AG#
CTm5CGAG
CAm5CGTG
CGTAm5CG
m5CTGCAG
CACGTG
CGTACG
CTGCAG
CGATCG b
yIl
Sites
cut
CGm6ATCG
CGATm4CG
GTCGm6AC
GTAmC b
CGm6ATCG
m5CGGWCCG
CGGWCCG
SQI
GAGCTC
CCGCGG
GTCGAC
SaDI
Sa3AI
TCGCGA
GATC b
S96I
GGNCC
GTm6Am5C
TCm6ATGA
TCATGm6A
Gm6AATTC
GAm6ATTC# b
GAATTC
Gm6AGCTC
CGGWm5CCG
CGGWCm5CG
GAGm5CTC
I?
m5CCGCGG
GTCGAm5C
GTm5CGAC
TCGCGm6A
Gm6ATC
Br8,Bu3,Eh3
CGATm5CG
CAGn4CTG#
CAGm5CTG
RsrI
Nel
Nel
St7
Ro3
Nel
Gi3
Ghl
Fol
Nel
Dol ,Gr4,Mcl 1,Ne2
CTCGCm6AG#
CAGCTG
&B4273I GTCGAC
GTAC b
RsaI
CGATCG
RSIh
TCATGA
Rsj2KI
References
GTCGm6AC#
T'5CGCGA
GATm5C# b
GATm4C
GAThm5C
GGNm5CC#
GGNCm5C
GGNhm5Chm5C
Br8,Bu5,Dol
Eh3,Ja3,Rol
Ba6
Eh3,Ne4,Ne5
Lyl
Pa2
Ne4
Mcli
Ba5
Mc 1 ,Qi3
Mcil
Kll,Ne2
Br8,Eh2,Lu2,Qil
Mc3,Ro4,Ro5,Va4
Mcl3,Nel,Qi3
Drl,Eh2,Ja3,Mc3,Ro3,Se 1
Ne5
Hul
Ko3,Ne2,Pel
TCGCGm6A
AGTAm5CT
m5CCNGG
T'5CGCGA
SaczFI
TCGCGA
AGTACr
CCNGG
Hul
Mc 1 1,Ne 1
Cm5CNGG
Wol
Mc 1 1,Ne2
SfaNI
GATGC
GATGm5C
Gm6ATGC
£213I
Cm4CNGG
ScI
GGCCN5GGCC
GGm5CCN5GGm5CC b GGCm5CN5GGCC
Nel
Mcll1,Po4
Mcl l,Qi2
GGCCN5GGCm5C
Sfll
?
CrGCAG
CTGCm6AG
Br8
Nucleic Acids Research, Vol. 19, Supplement 2059
Restiction Recognition
enzyme sequence
SaAI CRCCGGYG
GGWCC
Sid
CCCGGG
SmaI
Sites
cut
Sites not
cut
References
CRCm5CGGYG
Ta3
Ka5,Ka6
Br8,Bu6,Eh2,Ga4
Ja3,Ka7,Mc3,Qul
GGWm5CC#
m4CCCGGG
Cm5CCGGG
m5yCCGGG b
Cm4CCoGG b
CCm4CGGG
CCm5CGGG b
SnaBI
S~I
II
TAm5CGTA
TACGTA
GTGCAC
ACTAGT
GCATGC
GTGm5CAm5C
m6ACrAGT
Am5CTAGT
GCATGm5C
G(n6ATGC
CGTm6ACG
TCGCGm6A
9
Ghm5CATGhm5C
CGTACG
TCGCGA
S soIl
CCNGG
sphI
GAATTC
AATATT
GAGCTC
SQI
AGGCCT
m6AATATT
GAGN6RTAYG b
RSPI AACN6GTRC b
1m5CGA b
TCGA
TQI
Tfun5CGA b
GACCGA
TaqII
CACCCA
m5C?CWG
CCWGG
IaXI
TfiI
Tifi
IfI
Th,FJ
XbaI
flhHI
GAWTC
TCGA
CGCG
TCGA
TCTAGA
T'5CGCGA
TCGm5CGA
Cm5CNGG
m5CCNGG
Gm6AA
TCGm6A#
Gr4,Hul,Mc3,Va3
Gm6ACCGA
Hul
Ne4
Grl
Fol
TCGm6A
Tm5CGA
Ne4,Qi3
Nel,Ne4
Vil
Gr3
Ni4
Nel
Br8,Rol
GAGm5CTC
GAGhm5cThm5C Hul
AGGm5CCT
Ca4,Mcll
So3
AGGCm5CT
Nel
AGGCm4CT
Nal,Na2
Gm6AGN6RmTAYG# b
Nal,Na2
Am6ACN6GmTRC# b
Cm5CWGG
GAWTM5C
m5CGCG
Fol
Ho2,Wol
Hol
Wol
Mcl 1,Ne2,Mo3
m5CGCG
Sa3,Va6
Gal,Nel
hm5CGhm5CG
Hul
TCGm6A#
Sa3
Mcl3,Wel
Gr4,Hul,Ne2
TCTAGm6A#
Tm5CTAGA
Thm5CTAGA
2060 Nucleic Acids Research, Vol. 19, Supplement
Restriction Recognition
enzy-me sequence
CTCGAG b
XhQI
?
XhoII
RGm6ATCY
XmaI
RGATCY
CCCGGG
Sites
cut
CCm'5CGGG b
Sites not
References
cut
CTm5CGAG
CTCGm6AG
m5CTCGAG
RGATm5Cy b
m4CCCGGG
Br8,Eh2,Eh3,Ka7
Mc3,Va3
Br8
Bu6,Yo5,Yo6
m5CCCGGG
Cm4CCGGG
CCm4CGGG
XmafiE
XmnI
CGGCCG
GAAN4TTC
?
GAm6AN4YrC
CGGm5CCG
Gm6AAN4TI C
Ne2,Tr2
Mc1l,Ne2
GAAN4TP 5C b
XorII
CGATCG
CGm6ATCG
CGATm5CG
Br8,Eh2
hm5CGAThm5CG Hul
FOOTNOTES
a. # denotes canonical modification MTase
specificity. M= A or C, K= G or T, N= A,C,G, or T, R= A or G, Y= C or T, W= A or T, S= G or C, D=
A,G or T, H = A,C or T. Sequences are in 5'-3' order. m4c = N4-methylcytosine; m5C = CS-methylcytosine; hm5C =hydroxymethylcytosine; mc = methylcytosine,
N4 or C5-methylcytosine unspecified; m6A= N6-methyladenine. Nomenclature is according to (Sm2) and (Co4).
b. AccI nicking occurs slowly in the unmethylated strand of the hemi-methylated sequence GTMKAm5C.
Afll cuts slowly at GGWCn4C.
Ahai (GRCGYC) will cut GRCGCC faster if these sites are methylated at GRCGm5CC (Ne5), but will not cut GRCGYm5C sites (Ne2,Ne5).
Asp718I cuts M CviQI -modified (GTm6AC) Chlorella virus NY2A DNA. Asp7l.8I does not cut GGTACm5CWGG overlapping dcm sites (Mu l) or m5C-substituted
phage XP12 DNA, whereas 4Knl cuts XP12 readily (Ne4).
AvaI nicking occurs slowly in the unmethylated strand of the hemi-methylated sequence CTCGm6AG/CTCGAG (NeS).
AvaH cuts slowly at GGWCm4C.
Bacillus species have been surveyed for Gm6ATC and Cm5CWGG specific methylases. Many species have Gm6ATC specific methylases but none had Cm5CWGG
specific methylases (Di3).
Ball sites
overlapping dcm sites (TGGCm5CAGG) are 50-fold slower than unmethylated sites (Gil).
rate effects when its recognition sequence is n4C- or m5C-methylated at different positions.
BglI cleavage rate at certain GCm5CN5GGC, GCm4CN5GGC, and GCCN5GGm5C hemi-methylated sites is extremely slow. However, m5C bi-methylated
M HaeIl-BglI sites are completely refractory to BglI (Ko3,Ne2).
BssHIl does not cut M-HhaI-modified DNA, in which two different cytosine positions are hemi-methylated, Grm5CGCGC/GCGmICGC (Ne4).
M BstI modifies the internal cytosine GGATmCC, but it is not known whether this modification is m C or m4C (Le2).
BstEII cuts the fully m5C-substituted phage XP12 DNA (Ne5).
BstNI cuts Cm5CWGG, n'5CCWGG and m5Cm5CWGG (Ne5). BstNI isoschizomers that are insensitive to Cm5CWGG include AorI, ApyI, BspNI, MvaI and TaqXI
(Mc4).
BsuRI nicking occurs in the unmethylated strand of the hemi-methylated sequence GG(m5CC/GGCC.
Cfi9I, see reference Bu6 for rate effects.
M CreI is from the unicellular eukaryote Chlamydomonas reinhardi (Sa2).
DpnI requires adenine methylation on both DNA strands. Isoschizomers of DpnI include CfiI, NanII, NmuEI, NmuDI and NsuDI (Cal). DpnI cuts dam modified
XP12 DNA (Ne6).
M Eco dam modifies GATn5C at a reduced rate (NeS). Many other bacteria that modify their DNA at Gm6ATC are listed in references Bal and Lol.
EcoA, EcoB, EcoD, EcoDXXI, EcoK are Type I restriction endonucleases. 'T represents a 6-methyladenine in the complementary strand.
EcoPI is a Type HI restriction endonuclease (Ba2,Bal,Ha2).
EcoP15 is a Type Im restriction endonuclease (Hu2).
EcoRI cannot cut hemi-methylated Gm6AATTC/GAATTC sites. Bimethylated GAm6ATTC/GAm6ATTC sites are not cut by EcoRI or RsrI (NeS). EcoRI shows
a reduced rate of cleavage at hemi-methylated GAATTm5C (Trl) and does not cut an oligonucleotide that contains GAATTm5C in both strands (Brl).
EcoRII isoschizomers that are sensitive to Cm5CWGG include AtuBI, AtuIl, BstGH, BinSI, Cfr5I, Cfril I, EclII, EcalI, Eco27I, Eco38I and MphI (Ro3). EcoRJI
shows reduced rate of cleavage at hemi-methylated m5CCWGG/CCWGG sites (Yol).
EcoRV cuts the fully m5C-substituted phage XP12 DNA (NeS).
EcoR124 and EcoR124/3 are Type I restriction endonucleases. mT represents a 6-methyladenine in the complementary strand.
is a Type I restriction endonuclease.
FokI cuts about two-fold to four-fold more slowly at CATCm5C than at unmodified sites (Ne5).
M FokI in ref Po3 corresponds to M-FokIA in ref Po4.
Haell show a reduction in rate of cleavage when its recognition sequence is modified at RGCGmSCY.
HaeIi nicking occurs in the unmethylated strand of the hemi-methylated sequence GGm5CC/GGCC.
Hinfl cuts GANTn5C, however, detectable rate differences are observed between unmethylated, hemi-methylated (GANTm5C/GANTC) and bi-methylated
(GANTm5C/GANTm5C) target sequences. Hinfl does cut phage XP12 DNA, although at a reduced rate (Gr4,Ne5). Hinfl cuts unmethylated GANTC faster than
hemi-methylated GANTm5C/GANTC, which is cut faster than GANTm C/GANTm C. However, the rate difference between unmethylated and fully methylated
Hinfl sites is only about ten-fold (Hul,Ne5,Pel).
Hpai nicking in the unmethylated strand of the hemi-methylated sequence m5CCGG/CCGG is in dispute (Be3,Bu6,Ko3). Hpall cuts hemimethylated mCCGG 50
times slower and fully methylated mCCGG 3000 times slower than unmethylated DNA (Ko3). See reference (Bu6) for HpaIl rate effects.
BanI gives various
Nucleic Acids Research, Vol. 19, Supplement 2061
KpnI sensitivity to hemi-methylated GGTAmSCC and GGTACm5C sites has been reported. KpnI efficiently cuts m5C-substituted phage XP12 DNA, but not Chlorella
virus NY2A DNA, which carries both GTm6AC and m5CC modifications (Ne4).
MaeII nicks slowly in the unmethylated strand of hemi-methylated Am5CGT/ACGT (Mo2).
MboI isoschizomers that are sensitive to Gm6ATC include BssGH, BsaPI, Bsp74I, Bsp76I, BsplO5I, BstXll, BstEI1I,BssGII, CpaI, CtyI, CviAI, CviBII, CviHI, Dpnll,
FnuAll, FnuCI, Had, Meul, MkrAI, Mmell, MnoIII, MosI, Msp67II, MthI, MthAI, NdeII, NflAII, NflBI, Nfl, NlaDI Nlal, NmeCI, NphI, NsiAI, NspAI,
NsuI, PfaI, RlulI, SalAI, SalHI, Sau6782I, SinMI, Trull (Ro3).
MboII cuts the fully m5C-substituted phage XP12 DNA (Ne5), although certain hemi-methylated m5C-containing substrates are reported not to be cut (Gr4).
MflI cuts slowly at m6AGATCY sites (Onl).
Mammalian methylase is the m5CG methyltransferase from Mus musculus. (mouse) (Be6).
MspI cuts the hemi-methylated sequence CmSCGG/CCGG (WaS) and Cm4CGG/CCGG duplexes (Bu6). MspI cuts very slowly at GGCm5CGG (Bu2,Kel). An M MspI
clone methylates m5(CG( (WaS,Wa2). However, there is a report that Moraxella sp. chromosomal DNA is methylated at m5Cm5CGG (Je2).
MvaI nicking occurs in the unmethylated strand of the hemi-methylated sequence m4CCWGG/CCWGG and CCm6AGG/CCTGG (Ku3). MvaI cuts XP12 DNA very
slowly at m5Cm5CWGG.
NanH requires adenine methylation on both DNA strands (Cal). NanII cuts M Eco dam modified XP12 DNA (Ne5).
NciI may cut m5Cm5CGG methylated DNA (Br8,Je2). Possibly the second methylation negates the effect of Cm5CGG.
NcoI is blocked by M SecI (CCNNGG) (Ne5).
NcrI is a BgEl isoschizomer from Nocardia carnia Beijing (Qil).
NdeI cuts the fully m5C-substituted phage XP12 DNA (Ne5).
NdeHl cuts the fully m5C-substituted phage XP12 DNA (Ne5).
Ngo. There is some confusion about naming restriction enzymes from these strains. NgoPII, NgoII and NgoSI may be the same. NgoPIl may be NgoIII.
NgoPll does not cut overlapping dcm sites (Su4).
NmuDI requires adenine methylation on both DNA strands (Cal).
NmuEI requires adenine methylation on both DNA strands (Cal).
PaeRI cuts hemimethylated CTm5CGAG/CTCGAG sites 100 fold slower and cuts fully methylated CTm5CGAG/CTm5CGAG 2900 fold slower than unmethylated
sites (Ghl). Hemi- or full methylation at m6A completely protects against PaeR7 cleavage (Ghl).
RsaI cuts the fully m5C-substituted phage XP12 DNA (Ne5), but does not cut Chlorella virus NY2A DNA, which is modified at GTm6AC (Ne4,Xil). DNA from
Rhodopseudomonas sphaeroides species Kaplan is cut by Asp718I, but not by RsaI or KpnI (Ne4). It is likely that M RsaI specifies GTAm4C; and high levels
of m4C are present in R. sphaeroides DNA (Eh3).
RsrI cannot cut hemi-methylated Gm6AATTC/GAATTC sites.
Sau3AI nicking occurs in the unmethylated strand of the hemi-methylated sequence GATm C/GATC (St3). Sau3AI cuts at a reduced rate at "6AGATC (OnI). Sau3AI
isoschizomers that are insensitive to Gm6ATC include Bce243I, Bsp49I, Bsp5lI, Bsp52I,Bsp54I, Bsp57I, Bsp58I, Bsp59I,Bsp6OI, Bsp6lI, Bsp64I, Bsp65I, Bsp66I,
Bsp67I, Bsp72I, BspAI, Bsp91I, BsrPH, Cpfl, Csp5I, CpeI, FnuEI, MspBI, SauCI, SauDI, SauEI, SauFI, SauGI and SauMI (Ro3).
SfiI cannot cut M Bgll-modified DNA (Nel).
SmiaI nicking occurs in the unmethylated strand of the hemi-methylated sequence CCmSCGGG/CCCGGG (Bu6,Wa5). SmaI may cut CmSCmSCGGG methylated DNA
(Br8,Je2) Possibly the second methylation negates the effect of CCm5CGGG. There are conflicting results regarding SnaI: m5CCCGGG is not cut when modified
by M AquI methyltransferase (Ka7) or at overlapping M HaeIII-SmiaI sites (GGm5CCCGGG, Ne5). Other investigators have reported that SmiaI cuts at a reduced
rate at hemi-methylated m5CCCGGG sites (Bu6).
SplI cuts GTm6AC-modified Chlorella virus NY2A DNA, but does not cut KpnI-digested XP12 DNA (Ne4).
StySBI and StySPI are Type I restriction endonucleases. mT represents a 6-methyladenine in the complementary strand.
TaqI cuts very slowly at Thm5CGA (Hul). TaqI cuts the fully m5C substituted phage XP12 DNA (Hul,Ne5).
M-TaqI methylates Tm5CGA at least 20 fold slower that unmodified TCGA (Mc7).
XbaI will cut Tm5CTAGA/TCTAGA hemi-methylated DNA at high enzyme levels (> 100U Xba 1/ug), but will not cut this sequence in twenty to forty-fold
overdigestions.
XhoIl nicking occurs slowly in the unmethylated strand of the hemi-methylated sequence RGATmSCY/RGATCY.
XmaI is claimed not cut CCm5CGGG in one report (Br8). See reference Bu6 for rate effects.
XmnI cuts the fully m5C substituted phage XP12 DNA (Ne5). XmnI cuts slowly at some sites in DNA methylated on both strands at GAAN4TTm5C (Ne5).
2062 Nucleic Acids Research, Vol. 19, Supplement
TABLE II: DNA methyltransferases and their modification specificities
Cloned methylases in bold.
Methylase a
Specificity a
GACGTC
M-A=I
GTMKm6AC
M-AaK21
M-&R
M-Alw26I
A1TAAT
CCSGG
CYCGRG
GGWCC
CYCGRG
TGGm5CCA
Gm6ATC b
GGATm4CC
GmCWGC?
GGYRCC
GRGCYC
References
Lu2
Lu2
Lu2
Sli
Kr2,Lu2
Bu4
Bu4
Mc8,Tr2
Ka7,Ka8
Mo3
Mo3
Lu2
Lu2
Lu3
Lu2,Mc8
Di3
Hal,Lu2,Na3
Hal
Lu2
Lu2
Gm5CWGC
Dol,Hal,Va5
GmCWGC
Gm6AT
Am6AG
Cm4CSGG
m5CGCG
GCCN5GGC (m4C)
GGWCmC
GGATmCC
Hal,Va5
Hal
Hal
Ja4,Ja6,Ja7,Pe2,Po6
Ku2
Lu2
Ma9
Kil
Fe2,Ko 1 ,Po2,Qi3,S z4,Ve 1
Pa2
Ja3
Le2
Ba7
Va2
Xul
CITAAG (m6A)
GATiP"C
AGmSCT
GT'i5CTC
and Gm6AGAC
M ApaI
MAgul
Asell
M*RALu,
M-AvaI
M
M.AI
M*EAwI
MOAI
M-BamHl
M.A.=I
M-BalIs
M-BbvI
M-BbvSI
M-Bbv
M-'Bb
M-BI
MIRa
M *D..a,I
M-BSRI
M.B106I
M.BA6I
M-*I
M*flVI
M-LYI
M-BsuBI
GGGm5CCC
m5CYCGRG
GGm5CC
ATCGm6AT
GCNCG
GGANPCC
CTCGm6AG
RGATmCY
CTGCm6AG
M-*MEI
m5CGCG
m5CCGG
M*DhMI
YTm5CGAR
GGm5CC
and Gm5CNGC
M
BzIFl
M-'wp3T
Gal,,Gu7,Lkl,Jel
Gu7,Ik1,Jel,Wa7
Gul,Gu2,Gu7,Jel,Shl
Bel,Gu5,Gu4,No2,No3
Nol,Trl
Nucleic Acids Research, Vol. 19, Supplement 2063
Methylase a
M Bslu.p lI
M .lDjplls
M-BMQI
M-BsuRI
M-BjSPf3
Specificitv a
GGm5CC
and Gm5CNGC
GGCC
and GDGCHC
mCCGG
GGm5CC b
GGm$CC
and Gm5CNGC
M-ILMSPRI
GGm5CC
M *nSPRl91
and mSCmSCGG
and Cm5CWGG
m5Cm5CGG
and CmCWGG
M-BsuSPR83I
GGm5CC
M-
A
M*fI
M. 6I
M-Cfr9I
M-L flOI
M-2 1 3I
M-ClaI
M-CreI
M-Ctv
M CviBI
M *_viBIII
M*fviJI
and Cm5CWGG
GCAN8GTGG
YGGm5CCR
CAGm4CTG
Cm4CCGGG
Rm5CCGGY
GGNm5CC
ATCGm6AT
Tm5CR
Gm6ATC#
Gm6ANTC
TCGm6A
RGm5Cy
M CviPI
m5cc
M-CviQI
M-CviRII
GTm6AC
TGCm6A
GTm6AC
M-DdIk
M-D2gnII
M-DInA
m5CTNAG
Gm6ATC
?Gm6ATC?
M*£viRI
M-EaeI
MQIg
M-EcaIdmIII
M
*EagImr
M*Lg
damI
MEca
M-Ek dcm
M-Ef&A
M-EQB
M-EcoD
YGGm5CCR
CGGCCG
GGTm6ACC
Gm6ATC
Cm5CWGG
RmCCGG
mCCWGG
GGWCmC
Gm6AGN7GmTCA b
TGm6AN8mTGCr b
TTAN7GTCY b
Reference
Gu4,Gu5,Gu7,Nol,No2
Bel
Je2
Gu6,Ki2,Ki3
Gu4,Gu5,Gu7,Je2,Ki2,N16
No2,Trl ,Tr3
Bel,Gu5,Gu7,No2
Pol
Be2,Bul,Gu3,Gu5,Ki2,Pol
Je2,No2,Pol
Gu3
Da2,Da3
Po6
Bu5
K13,Po6
Po6
Bi5
Mc3
Sa2 (Chlamydomonas)
Ri2
X2
Na4
Sh3
Xi4
Xi2,Xi5
Stl
Stl
Ho3,Lu2,Sz3
Del,La3,La4,La5,Ma6
Del
Jal,Whl
Sz2
Br2
Br6,Bu9,Drl ,Gi2,Ha2,He2,Url
Bo5,MalO,So2,Url
Bu8,Ne8
Ni2
Mol,Ni2
Co7,Fu2
Go3
Go3
2064 Nucleic Acids Research, Vol. 19, Supplement
Methylase a
M-*E&DXXI
Specificitv a
TCAN7ATTC b
GAGN7ATGC b
Am6ACN6GmTGC b
AGm6ACC b
Gm6ATC b
M*EM.cPI
M-E.j Pl
M.EoP1d5
M
-EnRlS
M-E&QRI
GAm6ATTC
M-EcoRII
Cm5CWGG
M-E.QRV
Gm6ATATC
GAAN6RTCG (m6A)
M As2R124
M-EcoR124/3
M.fEMT1 d.
M'EFs&T2 ~z
M-*EUT4iln
M-Eco3 lI
Cm6AGCAG
GAAN7RTCG (m6A)
Gm6ATC
Gm6AT
Gm6ATC
GGTm5CTC
M*EwiDI
MEnuDIII
m5CGCG
M-ESL64I
M.ES&72I
M -Er&98I
M*E. 105I
M-EM3I
M-EFokI
M-E&kI
MTFV3
M-Ii.III
M-HapII
M-HdI
M.kgC
M-HgiEI
M-lhagI
M HhLIIn
M*Hi,LCH
Skl
Fu2
Bo2,Go3,Kal,Lo2,Sal
Ba2,Hu2
Co5
Hu2
Dul,Gr2,Ke2
Ne2,Ne9,Rul
Bh 1 ,Bu7,Bu8,Ko6,Ko7,Ko8
MalO,Sc6,Sol,Yo4
and Gm6AGACC
GGNCC
CTGAAG (m6A)
CTGAAG (m6A)
GGYRCC
CACGTG (m5C)
AAGCT[
TACGTA
GGTm6CTC
GAGm6ACC
GGCC (m5C)
M-E..v..47l
M-Eco5I
M-Eg&57
M *coS7I
References
GCGC
GGm6ATG
and Cm6ATCC
TGCGCA
??Mr??
*-
*
*
RGCGCY
GGm5CC b
CmCGG
GACGC (mC)
GWGCWC
Bo3
Pr2,Pr3
Pr2,Pr3
Scl,Sc7
Br7,Ha2,Ha3,Mi 1,Sc4,Sc5
Ha4,Mal ,Mi2,Sc3,Sc4,Sc5
Bu4
Bu4
Po6
Po6
Po6
Po6
Po6
Po6
Po6
Ja3
Lu2,Val
Lu2,Nel
Lu2
La6,Lo3,Lu2,Ma8,Nwl
Mel
EsI (Frog virus)
Lu2,S13
Lu2,Ma5,S13
Wal
Lu2,Nwl
Lu2
GGYRCm5C
Er
GGWCm5C
GGWCm5C
Gm5CGC
Gm6ANTC
GTYRm6AC
Erl
Er
Ba9,Ca3,Lu2,Sml,Wu 1 ,Zal
Chl,Kel ,Ma3,Ma4,Sc9,Sml
Gr4,Mc8,,Ro7 Re2
Nucleic Acids Research, Vol. 19, Supplement 2065
Methylase a
M-lijndll
M-JjndIH
M ljfI
M-ElnPI
M.H2
GTYRm6AC
m6AAGCIT
Gm6ANTC
GCGC
GATATC (I6A)
GTfAm6AC
References
Lu2,Re2,Ro6,Ro7
Lu2,Ro6Ro7
Chl,Lu2
Ba9,Lu2
Dal
Br8,Yo3
Lu2,Ma5,Qul,Wi2,Yo2
Mc8,Ne2,Ne4
La8 (Bacius phage)
M-MboII
cm5CGG
Tm5CACC
GGCC
GCNGC
GDGCHC
TCCGGA
Gm6ATC
Po6
Mc8
GAAGm6A
Mcl2,Ne4,Ne2
M*MQll
m5CG b
M-HphI
M-H2
M-Kpn2I
M-NgQBI
Gm6ATC b
GmCWGC b
TP5CACC b
M-N2BII
GTAN5m5CTC b
M *laIII
GGCC
Cm6ATG
M-NaIV
Gm5CCGGC
GGNNm5 CC
Be6 (Mouse)
Eh2,Je2,Lu2,Nw2,Wal ,Wa5
Mel
K13,Po6
Lu2,Lu4
Lu2,Val
Se2
Lu2,Val
Sil
Pi5
Ril
Su2
Ko5,Ril
Pi3
Su3,Su4
Ko5,Ril
Ch2,Kol5,Ril
Ko5,Pi2
Ko5
Ko5
Pi3
Pi3
Mo3
Lal,Lu2,Mo3
Lu2
Mo3
cTCGm6AG
CTGCm6AG
CAGm4CTG
GTCGm6AC
Gi3,Thl,Th2
Lel,Wa3,Wa4,Wa6
Bll,Ta2
Ba6
M MstIT
M.MvaI
m5CCGG b
TGCGCA
Cm4CWGG
GCN7GC (m4C)
GCCGGC
M-*2gII
M-NgoAI
??m5.??
CCATGG (mC)
CATATG (m6A)
GGNNCC b
RGCGCY b
RGmCGCY b
GGm5CC b
GGm5CC b
M.jgZPII
GGm5CC b
Neurospora
M .gI
*I
M-
M-*NMVI
M-.g2I
M.NzgPI
M*fQfi
M.NgQIV
MNjgqV
M.NgQVI
M-* VII
M-EUR7
M*PaR7
M-EmIx
M pvuII
M-E&4273I
CCGCGG b
Gm5CCGGC b
GGNNm5CC b
Ll1
2066 Nucleic Acids Research, Vol. 19, Supplement
miScitv a
M-iaII
M.hTI
M-Ifi
M*53A
M*gg6I
M SfjI
M*5jT
GAm6ATTC
CCGCGG
GTCGm6AC
GAPm5C
GGNm5CC
GGCCN5GGCC (m4C)
GGWmSCC
Lu2,Nel,Szl
Ba8
Ka5,Ka6
CCmCGGG
Hel,Po6
GCATGC
Gm6AATTC
CmCNGG
Lu2
Ka9,Bu4
M*XaI
M *5a471
M'5o47II
M*&MQI
m5CG
M*51ySBI
M-T^li
M*ityPI
CCWWGG
Gm6AGN6RmTYG b
Am6ACN6GmTRC b
Am6ACN6RmTAyG b
Gm6AGN6GmTRC b
M*TflI
M-MmaQ
Tetrahymena
M*XmaI
M XmaI
Ba5,KalO
Lu2
Lu2,Ro4,Ro5
Sel
TCGm6A
TCGm6A
TCGm6A
??m6A??.
TCrAGm6A
CCCGGG (m4C)
CGGmCCG
GAAN41TC
Ka9,Nil,Ni3
Nul,Pi5,Re3
Rel
Ful,Fu3,Ga3,Nal,Na2
Ful,Fu3,Nal,Na2
Ful,Fu3
Ga3
Lu2,Mc3,Sa3,S12
Mc3,Sa3
Sa3,Va6
Ca2,Gol
Lu2,Mcl3,Val
Ba8
Mc8,Tr2
Fel
NOTES a. See footnote "a" of Table I. b. See footnote "b" of Table I.
Nucleic Acids Research, Vol. 19, Supplement 2067
TABLE III: Methylation sensitivity of Type 11 DNA methyltransferases.
Methylase(specificity)a
Not blocked by prior
modification at b
M*AluI (AGm5CT
M-BamHI (GGATm4CC) GGm6ATCC
GGm6ATCC
M-BI (GGATmCC)C
M.Cft6I (CAGm4CTG)
m6ATCGAT
M-CLaI (ATCGm6AT)
ATm5CGAT
Tm5CGA
(TCGm6A)
M-_viBIl
M*EoRI (GAm6ATTC) GAATIm5C
M-*gRII (Cm5CWGG)
GATm5C c
M-Eco dam (Gm6ATC)
Blocked by prior
modification at b
AGm4Cr
GGATCmSC
CAGm5CrG
References
Bu5
La7,MclO
Le2
Bu5
M9,Mcl 1,Wel
Cm4CWGG
MclO,Va4
Br2
Bu4
MclO
CATm5CC
Ne4
Po3,Po4,Sc2
Rol
Gm6AATTC
GATtm5C
M--EkIA (GGm6ATG)c
M-HhaI (Gm5CGC)
M.iUall (Gm6ANTC)
M-paIl (Cm5CGG)
M-HphI (Tm5CACC)
M-MboI (Gm6ATC)
M*MboII (GAAGm6A)
M-MsDI (m5CCGG)
M-MvaI (Cm4CWGG)
GATm4C
CATCm5C
GCGm5C
GANTIm5C
m5CCGG
GGTGm6A
GATm5C
T"5c1-1Tr5c
Cm5CGG
Cm5CWGG
Bu4
Nel
m5cm5CwGG
M-PvwI (CAGm4CTG)
M-UT2 4am (Gm6ATY) GAThm5C
M-EcoT4 dam (Gm6ATC) GAThm5C
M-TaaI (TCGm6A)
MclO
Mc9,MclO
MclO
MclO
MclO
MclO
CAGm5CTG
T5CGA c
Bu5
Do2,Mil
Sc4
Mc7
a. See footnote "a" of Table L.
b. An enzyme is classified as insensitive to methylation if it methylates the modified sequence at a
rate that is at least one tenth the rate at which it methylates the unmodified sequence. An enzyme is
classified as sensitive to methylation if it is inhibited at least twenty-fold by methylation relative to
the unmethylated sequence.
c. See footnote "b" of Table I.
2068 Nucleic Acids Research, Vol. 19, Supplement
TABLE IV: Isoschizomer/isomethylator pairs that differ in their sensitivity
to sequence-specific methylationr.
Mcahykd sqam-ce
I
m4CCGG
Cm5CGG
Cm4CGG
CCm5CGGG
Cm5CWGG
Gm6ATC
GATm5C
GAPm4C
GGCm5C
GGTACm5C
GGTAmSCm5C
GGWCm5C
RLstQi iaWIKLQsAIn a,b
NQJcu by
Cut by
M-Ri
Maul
MaI
XmaTI (k9I)
SPM3A
mm I:EmiEI)
MboI
Sa3A
HnoX
Aau718I
MI
RGm6ATCY
X2LQo]1 W&tYI)
Tm5CCGGA
TCm5CGGA
TCCGGm6A
Acc]Ill
TCGCGm6A
lrsoCGAA
CGGWCm5CG
Ban
Snai
.Spl
SinaI
LQRII
MboI (deIt)
h3A
BsaMlI QMLQI)
13I (SaLI)
As-ull
Avai (E&247
mm
LauMi
Cau45I
Rs-ril
kfevnoe
Nel
Eh2,Mc 1i
Bu6
Bu6
Bu4
Gel,LulMc9,Ro3
Ne4
Ne4
Su4
Mul
Ne4
B3,Ja5,Wh2
Mc9,Ne4
La2,Sc2
Sc2
Ke3,Ne4
Mcl 1,Ne4
SclO
Qi3
Methylated sequence C
Resiriction iso thylator pairs de
methylated by
NQt mehylated by
References
IP5CGA
M.CviB[ (TCGm6A) M-IqI
We2
a. In each row the first column lists a methylated sequence, the second column lists an
isoschizomer that cuts this sequence, and the third column lists an isoschizomer that does not cut
this sequence.
b. An enzyme is classified as insensitive to methylation if it cuts the methylated sequence at a rate
that is at least one tenth the rate at which it cuts the unmethylated sequence. An enzyme is classified
as sensitive to methylation if it is inhibited at least twenty-fold by methylation relative to the
unmethylated sequence.
c. See footnote "a" of Table I.
d. In each row the first column lists a methylated sequence, the second column lists an
isomethylator that modifies this sequence, and the third column lists an isomethylator that does not
modify this sequence.
e. An enzyme is classified as insensitive to methylation if it odifies the methylated sequence at a
rae that is at least one tenth the rate at which it modifies the unmethylated sequence. An enzyme is
classfied as sensitive to methylation if it is inhibited at least twenty-fold by methylation relative to
the unmethylated sequence.
Nucleic Acids Research, Vol. 19, Supplement 2069
TABLE V: List of restriction systems referred to in this paper.a
Note:
a. Restrction systems in Table V are arranged by recognition sequence length and alphabetically by
recognition sequence to aid in identifying isoschizomers.
CC
Cvi NY
RGCY
CATG
Nl---
CCTC
AGCr
CCGG
CGCG
Gm6ATC
GATC
GCGC
GGCC
GTAC
TCGA
1TAA
CCNGG
CTNAG
GANTC
GGNCC
CCWGG
CCSGG
GCAGC
GGWCC
AGACC
ACCTGC
CAGCAG
CATCC
GAAGA
GAAGAG
GAATGC
GACCGA
and CACCCA
GACGC
GATGC
GGATC
GTCTC
TCACC
GDGCHC
CYCGRG
GRCGYC
GRCGYC
GRGCYC
GTMKAC
GTYRAC
AluI
BsuFI, sQI,
HaPI, aII, MsI
AccII, eI, BUI, _B_E, h-nDII ThaI
vnI, blanLL LaI,
Nf uEI
Br243I, RuPI, R67L BAL RPII, RPli, DGI, DEII
&LXII:,sCKQj_.I,, CviAI,, 12M.Hl, fMAII, f=CI, ErmaEI, MboIL M-m-eII,
I
Avail,e2l
I, fLIS
M 6I, Eh,Q47I, hjjil, kIjgjE, SAIn
S:inNff
HhI
PI
CviQIP1
mMsI
5crFI
AviBI, InI, Hitl
H13I, Su96I
AacI, -AorI, AYI, A=BI, AWL RiSL, Bsj2NI, BsGIII, BhNI, 51I,
I,EcaII,EclII,EcoRII &g27I,, Ec3I M_I,MaI, T XI
ZII
Mki,
Nxil
BcnI, SI.
BgIJi
A-vaE[,
B-me216I, EQ47I,, HdCIEI HgEl, SiLnl
TkI)igiliJ
EcoPI
HnPC15
FQkI
MbolII .NcuI
EarI
BsmI
HgaI
AMI
BamAI
H12hl, NgoQBI
S12861
&UL A-vaI
AbA
HLCH
2070 Nucleic Acids Research, Vol. 19, Supplement
GWGCWC
RCCGGY
RGCGCY
RGATCY
YGGCCR
RGGNCCY
AAGQT
ACGCGT
ACTAGT
AGATCT
AGCGCT
AGGCCT
ATCGAT
ATGCAT
CAGCTG
CATATG
CCATGG
CCCGGG
CCGCGG
CGATCG
CGGCCG
CGTACG
CTCGAG
CTGCAG
CrrAAG
GAATTC
GACGTC
GAGCTC
GATATC
GCATGC
GCCGGC
GCGCGC
GCTAGC
GGATCC
GGCGCC
GGTACC
GGGCCC
GTCGAC
GTGCAC
GTTAAC
TCATGA
TCCGGA
TCGCGA
TCGCGA
TCrAGA
TGATCA
TGCGCA
TGGCCA
rfCGAA
TTTAAA
CCAN6TGG
CCTNAGG
GAAN4TTC
GATN4ATC
GCCN5GGC
HgiM
210
HliMI, .jgPI
i,
BWstYI, XMQI
Dril
WndIll
S1I
Axll, L47fI
SmI
Lull, LaXI
h
NdI SinI, ma
£k911,
"QI
-CO Lml X-BmaDI, EnI, LhIi, XQEII
Eflt SDIi
BsuMI, LuRII, PR7I, XhbI
BUBI, FitI, SflI
Afll
jQQRI, RLI, £bo47I
SAQ£I
EQQRV
SahI
Mb927311, NaeI
BssHll
NheI
BanHfl, LmFI, BamKI iamNi RLa Bil,
fbQ&It Nir
As7181, KpnI
A aI
Rrh42731, SaI
HpaI
BspHI, LaXI
Accl, MI, Kpa2l, II
AmzI, MhuI9273l
NI, SJlDI, S13I, SpQj
AaCI, Li,
BcIXllB BxGL -£pI
aII
Asall, fBLtBI, CW451
Diii
WfaX, llI
MStlI
XmnI
MimI
1503I
Nucleic Acids Research, Vol. 19, Supplement 2071
GCTNAGC
GGTNACC
CGGWCCG
GAAN6RTCG
GAAN7RTCG
AACN6GTGC
AACN6GTRC
GAGN7ATGC
GAGN7GTGA
GAGN6RTAYG
TCAN7ATTC
TGAN8TGCT
TTAN7GTCY
CRGCGGYG
GGCCGGCC
GCGGCCGC
GGCCN5GGCC
BEII, Ecal
X4VI, R
Il
&QR124
&gR124/3
EcgK
StSPI
EcoA
StySBI
EcoDXXl
EcoB
EcoD
SAI
F&I
NotI
LiI