THE JOURNAL OF BIOLOGICAL CHEMISTRY
Vol. 272, No. 38, Issue of September 19, pp. 23465–23468, 1997
© 1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
Minireview
Nucleotide Excision Repair in
Mammalian Cells*
Richard D. Wood‡
From the Imperial Cancer Research Fund,
Clare Hall Laboratories, South Mimms,
Herts EN6 3LD, United Kingdom
A versatile strategy for repairing damaged DNA, termed
nucleotide excision repair (NER),1 is found throughout the
natural world in organisms ranging from mycoplasma to mammals. In humans, NER is a major defense against the carcinogenic effects of ultraviolet light from the sun. This repair pathway acts with varying efficiencies on a wide variety of DNA
alterations and is especially important for bulky, helix-distorting lesions. The key event in NER is incision of the damaged
strand on each side of a lesion in DNA, releasing the damage in
a fragment that is ;24 –32 nucleotides (nt) long in eukaryotes.
Nucleotide excision repair defects of various types are found in
individuals with the inherited syndromes xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy
(1). Individuals with XP are sun-sensitive and generally show a
greatly increased incidence of UV-induced skin cancers. The
disorder has seven genetic complementation groups, designated XP-A through XP-G, and a variant form, XP-V. The
recommended nomenclature uses a hyphen to refer to cells of a
given complementation group (for example XP-A), distinguishing
this from the affected gene XPA and the normal protein product
XPA (2). This minireview focuses on the biochemistry of NER in
mammalian cells, with an emphasis on recent developments.
Mechanism of Core NER Reaction in Eukaryotes
Many details of the NER reaction mechanism are being
elucidated with purified proteins and reconstituted systems. At
a minimum, the dual incision reaction of NER requires the
factors XPA, RPA, XPC, TFIIH, XPG, and ERCC1-XPF in
mammalian cells or the homologous components in yeast (3, 4).
These are summarized in Table I. XPA and the single-stranded
binding protein RPA associate with one another and are able to
preferentially bind to damaged DNA. TFIIH includes the XPB
and XPD DNA helicases among its subunits (5) and is involved
in local opening of DNA around a site of damage. XPC, usually
bound to a protein partner hHR23B, may also be involved in
damage recognition and opening. The XPG and ERCC1-XPF
factors are structure-specific DNA nucleases and are responsible for cleaving on the 39- and 59-sides of a lesion, respectively
(Fig. 1). The excised fragment is replaced in a DNA repair
synthesis reaction mediated by DNA polymerase d or e holoenzyme (6), and the process is completed by sealing the repair
patch of about 30 nt with a DNA ligase.
NER Nucleases
The cDNA encoding XPF was recently isolated, completing
the list of cloned XP core factors (7, 8). XPF forms a tight
* This minireview will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. This is the first article
of four in the “Eukaryotic DNA Repair Minireview Series.”
‡ To whom correspondence should be addressed.
1
The abbreviations used are: NER, nucleotide excision repair; XP,
xeroderma pigmentosum; CS, Cockayne syndrome; nt, nucleotide(s).
This paper is available on line at http://www.jbc.org
complex with the ERCC1 protein, directly homologous to the
similar Rad1-Rad10 complex in the budding yeast Saccharomyces cerevisiae. Both the Rad1-Rad10 and ERCC1-XPF complexes have a structure-specific nuclease activity that cleaves
near the border between single-stranded and duplex DNA
when the single strand has a polarity 59 to 39 moving away from
the border. Junctions between duplex and single-stranded
DNA are cleaved with the opposite polarity by the XPG protein
and its S. cerevisiae homolog Rad2.
The structure-specific cleavage properties of the NER nucleases have strongly suggested that they act on an opened, “bubble” intermediate during repair (Fig. 1D). Evidence for the
existence of such an intermediate has been provided by probing
for potassium permanganate sensitivity around a lesion during
repair in vitro. ATP-dependent opening of a region of approximately 25 base pairs occurs around the damaged site before dual
incision (9). Opening does not require the nuclease activity of
XPG (9) but is dependent on the DNA helicase activity of TFIIH.2
XPG and Rad2 are members of a family of enzymes that
includes the DNase IV/FEN1 group of structure-specific nucleases which function in DNA replication (10). Two conserved
domains in all of these nucleases are related to sequences in a
group of prokaryotic exonucleases, exemplified by the 59–39
exonuclease domain of Escherichia coli DNA polymerase I. The
solved structures of eubacterial enzymes in this family, such as
bacteriophage T5 59–39-exo/endonuclease (11), show that the
conserved domains are folded together in the predicted active
site and coordinate the binding of two Mg21 ions. The T5
enzyme has a helical arch with a size and ionic environment
appropriate for single-stranded DNA to thread through, starting at a free end. It will be interesting to learn how DNA is
bound during repair by XPG or Rad2, which must load onto
sites in DNA where there is no free 59-end. The intervening
region between the conserved domains in the various nucleases
in this family probably mediates specific protein-protein interactions for replication and repair. The XPG and ERCC1-XPF
nucleases require Mg21 or Mn21 but not ATP and on some model
substrates do not require other protein factors for their structurespecific cleavage activity (7, 9). With other substrates, RPA protein can dramatically stimulate nuclease activity (12).
Although the 39- and 59-incisions are nearly simultaneous,
the 39-incision mediated by XPG is normally first (13, 14). For
some lesions, the 39-incision can be carried out by purified core
incision factors in the absence of ERCC1-XPF (14), although
repair of a 1,3-intrastrand d(GpTpG)-cisplatin cross-link in
DNA required all components to be present to form either
incision (15). After the 59-incision, mediated by ERCC1-XPF
nuclease (7, 14), the damaged oligonucleotide is excised and
seems to be bound to one or more components of the repair
complex (14). In repair-proficient cell extracts some uncoupled
39- or 59-incisions can occur, indicating that the order of incisions is not always strict, although uncoupled 39-incisions are
more frequent than uncoupled 59-incisions (7, 14). The precise
positions of incisions for several different lesions have been
mapped in the human system. Depending on the adduct, incisions are introduced 2–9 phosphodiester bonds away from the
39-side of a lesion and 16 –25 phosphodiester bonds away from
2
23465
E. Evans and R. D. Wood, unpublished results.
23466
Minireview: Mammalian NER
TABLE I
Identified proteins participating in the dual incision reaction of mammalian NER
Human protein
Nearest S. cerevisiae
homolog
Comments
XPA
RPA
Rad14
Rpa
Preferentially binds damaged and single-stranded DNA
3-subunit single-stranded DNA binding protein; binds to XPA
XPC
Rad4
hHR23B
Rad23
Preferentially binds damaged and single-stranded DNA; not
needed for transcription-coupled repair or some DNA lesions
Binds to XPC and stimulates activity
TFIIH
XPB
XPD
p62
p52
p44
p34
Ssl2 (Rad25)
Rad3
Tfb1
Tfb2
Ssl1
Tfb4
DNA helicase (39 to 59); also known as ERCC3
DNA helicase (59 to 39); also known as ERCC2
TFIIH subunit; also known as GTF2H1
TFIIH subunit; formerly known as p41
TFIIH subunit
TFIIH subunit
XPG
Rad2
DNA endonuclease for 39 side of damage; also known as ERCC5
ERCC1
XPF
Rad10
Rad1
Subunit of DNA endonuclease for 59 side of damage
Subunit of DNA endonuclease for 59 side of damage; also known
as ERCC4
the 59-side. A unifying feature is that the modal length of
incision products is 26 –27 nt in each case (15).
XPC-hHR23B Complex and Transcription-coupled
Repair
The XPC protein plays a role in NER that is just beginning to
be revealed. This 106-kDa human protein copurifies with a
tightly bound 43-kDa partner, hHR23B. XPC binds DNA with
a preference for single-stranded (16, 17) or damaged DNA (16).
In some reconstituted repair systems, recombinant XPC protein alone is sufficient, and adding hHR23B does not increase
repair (16). In other fractionated and purified systems, only
weak repair occurs with XPC alone, and repair is significantly
stimulated by adding hHR23B (17). Intriguingly, the XPC subunit is dispensable for the repair of two different types of DNA
structures in vitro, an observation that has implications for the
mechanism of transcription-coupled repair in human cells.
Transcription-coupled nucleotide excision repair is a specialized mode of NER that removes DNA adducts significantly
faster from the transcribed strand of genes than from the
non-transcribed strand or the bulk of DNA. In mammalian
cells, transcription-coupled repair of pyrimidine dimers can
take place in the absence of XPC (while requiring the other
NER subunits including XPA and TFIIH) and is believed to be
initiated when RNA polymerase is stalled at a lesion in DNA
(18). A particular cholesterol moiety incorporated synthetically
into a DNA backbone is thought to cause an unusual degree of
helix distortion, and NER of this moiety does not require XPC
(14). Similarly, a model substrate consisting of a pyrimidine
dimer flanked on the 39-side by a 10-nt unpaired region is
repaired independently of XPC, while still requiring the other
NER subunits (19). Perhaps XPC is involved in forming or
stabilizing the damage recognition-incision complex at the 39side of a lesion and is not needed when the DNA structure is
already sufficiently altered on this side by a DNA adduct or by
a stalled RNA polymerase (Fig. 1B).
Accessory Factors and Cellular Interactions
An XP group that remains to be fully explained at the molecular level is XP-E. XP-E patients are generally mildly affected and show 50% or more residual repair capacity. Cells
from some but not all XP-E individuals are missing an activity
that binds damaged DNA, as measured in electrophoretic mobility shift experiments. This activity is associated with two
polypeptides of 127 and 48 kDa. Sequence changes in the
48-kDa subunit are present in cell lines that are missing the
DNA damage-binding activity (20). This XP-E-associated com-
plex is not required for the core NER system but may well play
an accessory role.
Further accessory proteins that modulate NER activity are
being uncovered. A factor designated IF7 was found to be
needed for appreciable repair of UV-irradiated plasmid DNA
(21) and stimulates incision at a cisplatin lesion in DNA by
about 6-fold,3 but a gene encoding this stimulatory protein
component has not been identified. The p53 protein or some of
the downstream target genes controlled by p53 may also be
accessory factors for NER. A study with human fibroblasts
showed that cells homozygous for p53 mutations have about
50 – 60% of the normal rate of excision of pyrimidine dimers
from the overall genome (22). Although p53 can bind to some
components of the NER apparatus, including TFIIH (reviewed
in Ref. 23), this binding may not have a direct effect on repair
efficiency. Instead, protein products of genes that are transcriptionally regulated by p53, such as Gadd45 and p21cip1/waf1, may
enhance NER. There is good evidence that in human cells, less
repair of UV damage to DNA occurs in the absence of Gadd45 or
p21cip1/waf1 induction (24 –26). Post-translational modifications
are also likely to regulate the activity of core factors. For example, the proper phosphorylation state of one or more components
is necessary to observe significant NER in a cell-free system (27).
NER in eukaryotes might work either by sequential assembly of individual factors or by the action of a preformed “repairosome” or by the interaction of intermediate subassemblies. Many interactions that would be consistent with any of
these possibilities have been documented between NER proteins. An extreme view is that all the required repair factors
can preassemble in the cell, and evidence has been provided for
such assemblies in yeast (28) and mammalian cells (29). An
intermediate hypothesis is that several subassemblies (for example Rad1-Rad10-Rad14 and TFIIH-Rad2 in yeast) exist in
the cell, which are then sequentially recruited to a repair site
(30). The details of observed interactions vary and depend on
the exact purification and analysis procedures. In particular,
moderate salt conditions disrupt some interactions that may be
significant. A line of study that could help clarify this subject is
a systematic and quantitative measurement of the binding
constants between different NER proteins.
The densely packed chromosome structure in the nucleus
introduces an additional level of complexity, in that chromatin
disassembly and reassembly need to be coupled with DNA
repair. A recent study analyzed nucleotide excision repair of
3
J. G. Moggs and R. D. Wood, unpublished results.
Minireview: Mammalian NER
FIG. 1. Model for the core nucleotide excision repair reaction
in mammalian cells. A, a site of damage such as a UV-induced
pyrimidine dimer (represented by the square black rectangle) causes
some local distortion of the helix. B, the damage is recognized by a
complex of NER proteins, thought to include XPA, RPA, and in most
cases the XPC-hHR23B complex. Limited opening of the DNA may
occur at this stage. XPC-hHR23B is dispensable for NER in special
instances, such as strand-specific transcription-coupled repair. C, a
larger region around the damage is opened up in an ATP-dependent
process that depends on TFIIH. D, the damaged strand is cleaved on the
39-side of the lesion by XPG nuclease and on the 59-side by ERCC1-XPF
nuclease, releasing the damage in an oligonucleotide 24 –32 residues
long. E, repair synthesis then takes place, mediated by a proliferating
cell nuclear antigen (PCNA)-dependent DNA polymerase d or e holoenzyme, and the repair patch of about 30 nucleotides is ligated to finish
the process. In yeast, similar events occur with homologous gene products (see Table I).
DNA in a cell-free system capable of chromatin assembly (31).
Chromatin formation occurred concomitantly with repair DNA
synthesis and required the chromatin assembly factor CAF-1.
Yeast lacking CAF-1 are viable but UV-sensitive (32). Like
DNA replication and transcription, NER might be preferentially localized at a limited number of foci in the nucleus. Using
immunofluorescence techniques, the XPG protein was observed
to change position in the nucleus after UV irradiation of cells,
suggesting that NER may occur at specific sites (33).
Cockayne Syndrome and Transcription-coupled
Repair
Cockayne syndrome is an NER-related disorder of particular
current interest. Like XP patients, individuals with CS are also
sun-sensitive but show a distinctive array of severe developmental and neurological abnormalities. Classical CS is caused
23467
by mutations in the CSA or CSB genes. The disease also occurs
simultaneously with XP in rare patients belonging to XP
groups B, D, and G. Remarkably, features of CS can therefore
be caused by particular mutations in at least five genes (1).
Cells in the CS-A and CS-B groups do not preferentially
remove DNA damage such as UV-induced pyrimidine dimers
from the transcribed strand of active RNA polymerase II-transcribed genes (34, 35). However, the clinical features of CS are
not simply explained by a defect in transcription-coupled repair
of pyrimidine dimers, since individuals with complete defects
in NER (e.g. most XP-A and some XP-G patients) do not have
CS symptoms. One possibility is that like XPB and XPD, CSA
and CSB are somehow involved in basal transcription and that
particular mutant forms of these proteins lead to subtle transcription defects that can account for the developmental abnormalities of CS (34, 35). The CS proteins have properties consistent with this view; the 44-kDa CSA contains WD repeat
motifs, and the 168-kDa CSB has motifs common with the
Swi/Snf family (34, 35). Such an explanation still leaves the
dilemma of the occurrence of CS in some XP-G patients, even
though XPG has no obvious role in transcription. There are
indications, however, that XPG may interact with some subunits of TFIIH (36). Moreover, with one purification protocol,
active yeast TFIIH copurified with overexpressed Rad2, the S.
cerevisiae homolog of XPG (30). It is possible that lack of a
proper XPG-TFIIH association can adversely affect transcription, giving rise to the CS symptoms in some XP-G patients.
Interestingly, it has been found that CS patients from XP group
G have mutations that would produce severely truncated XPG
protein, whereas XP-G patients without CS produce full-length
XPG protein with mutations that reduce or eliminate the nuclease function (37). The absence of full-length XPG might
affect transcription of some genes.
An alternative hypothesis is that CS is instead due to a
deficiency in transcription-coupled repair of some types of endogenous oxidative damage (37, 38). Some lesions induced in
DNA by active oxygen, such as thymine glycols, are subject to
preferential removal from the transcribed strand of active
genes. Unlike pyrimidine dimer removal, this strand-specific
repair of oxidative damage is apparently independent of XPA,
XPF, and the nuclease function of XPG but depends on CSA
and CSB. The repair is, however, disrupted in those XP-G cells
with severely truncating mutations (38). This suggests that
XPG may have a second function in addition to its role in NER,
aiding the transcription-coupled repair of some forms of oxidative damage. It might, for example, interact with a transcription complex blocked at a thymine glycol and accelerate thymine glycol-DNA glycosylase-mediated base excision repair at
such a site.
It has been further suggested that some lesions in DNA block
transcription and are not well removed by normal NER but
may only be efficiently dealt with by a CSA- and CSB-dependent repair mechanism. The CSA and CSB proteins might also
help RNA polymerase to occasionally bypass damaged sites on
a template without repair or play a role in releasing transcription complexes blocked at damage (35, 39). If blocking lesions
(for example, certain types of oxidative damage) accumulated
with age, these adducts could trap transcription components on
the DNA and gradually cripple transcription in CS cells (35).
This might help account for the severe neurological symptoms
and short lifespan of human CS patients.
How do the CSA and CSB proteins function in transcriptioncoupled repair? One possibility is that they are “coupling factors,” mediating an interaction between a stalled RNA polymerase and the repair proteins and thereby helping to attract
DNA repair to a damaged site on a transcribed strand. Such a
23468
Minireview: Mammalian NER
mechanism appears to operate during transcription-coupled
repair of pyrimidine dimers in E. coli, where the Mfd protein
acts as a coupling factor that promotes the interaction of RNA
polymerase with the NER factor UvrA (40). An indication that
the CS proteins actually do interact directly or indirectly with
RNA polymerase II is the observation that UV light induces
modification of the catalytic subunit of human RNA polymerase II by ubiquitination and that this modification is defective
in CS-A and CS-B cells (41). It is not yet known if the ubiquitination affects transcription activity or the ability to repair
damaged templates.
Connections between Mismatch Repair and
Nucleotide Excision Repair?
Single-base mismatches and short unpaired loops can arise
during DNA replication. To prevent mutations, human cells
use a repertoire of homologues of the E. coli mismatch repair
proteins MutS and MutL to recognize and initiate correction of
mismatches (42). Unexpectedly, disruptions of the DNA mismatch repair genes mutS and mutL were found to reduce
transcription-coupled NER of the lactose operon in E. coli (43),
and human cells with mutations in particular mismatch repair
genes were likewise found to have a deficiency in transcriptioncoupled repair of UV-induced pyrimidine dimers (44). S. cerevisiae mutants defective in the homologous mismatch repair
genes are not, however, defective in transcription-coupled repair of UV-induced DNA damage (45).
The mechanism of any influence of mismatch repair proteins
on NER is unknown, but it has been observed that the mismatch binding protein hMSH2 and a functional complex denoted hMutSa (a heterodimer of hMSH2 and hMSH6) can bind
to DNA base damage to some extent. This has been demonstrated for pyrimidine dimers and for a 1,2-intrastrand
d(GpG)-cisplatin cross-link (46, 47). The binding of hMutSa can
be considerably enhanced when the adducts are paired to noncomplementary bases (48, 49). However, in vitro studies have
yet to reveal any appreciable effect of such binding on NER.
Nucleotide excision repair is in fact 3–15-fold more efficient
when an adduct has noncomplementary bases in the opposite
strand, but this phenomenon appears unrelated to mismatch
repair because NER of such mispaired adducts occurs equally
well with extracts from cells either proficient or deficient in
mismatch correction (48, 50). Similarly, addition of purified
hMutSa to in vitro NER reactions does not suppress or enhance
NER (48). Further investigation of possible transcription-coupled repair defects in mismatch repair-deficient cells is required to establish a functional connection in mammalian cells.
Studies of physical interactions between mismatch repair proteins and NER proteins should be informative in this regard.
Acknowledgments—I thank the members of my laboratory and
Deborah Barnes, Stephanie Kong, and Alain van Gool for helpful comments. Charlie Haden and Robert Plant provided useful assistance in
preparing the manuscript.
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