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Biochemical Society Transactions (2013) Volume 41, part 6
Emerging roles for centromere-associated proteins
in DNA repair and genetic recombination
Fekret Osman* and Matthew C. Whitby*1
*Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
Abstract
Centromere proteins CENP-S and CENP-X are members of the constitutive centromere-associated network,
which is a conserved group of proteins that are needed for the assembly and function of kinetochores
at centromeres. Intriguingly CENP-S and CENP-X have alter egos going by the names of MHF1 (FANCMassociated histone-fold protein 1) and MHF2 respectively. In this guise they function with a DNA translocase
called FANCM (Fanconi’s anemia complementation group M) to promote DNA repair and homologous
recombination. In the present review we discuss current knowledge of the biological roles of CENP-S and
CENP-X and how their dual existence may be a common feature of CCAN (constitutive centromere-associated
network) proteins.
A brief overview of the kinetochore and
centromere-associated proteins
The faithful segregation of chromosomes during mitosis
and meiosis depends on an elaborate assemblage of
protein machinery, which ensures that sister chromatids
or homologous chromosomes are paired (depending on
the type of division) and then pulled to opposite spindle
pole bodies/centrosomes by microtubules that have been
correctly attached to them. Attachment of microtubules to
chromosomes is mediated by kinetochores, which are large
multiprotein complexes that are fabricated at centromeric
DNA [1]. At the core of this structure is the highly conserved
KMN network composed of KNL1, the Mis12 complex
(Mis12, Dsn1, Nnf1 and Nsl1) and the Ndc80 complex
(Ndc80, Nuf2, Spc24 and Spc25), with the latter being
responsible for directly interacting with microtubules. The
KMN network is anchored to the underlying centromeric
DNA via two distinct mutually exclusive and in some cases
redundant interactions with the Spc24-25 domain of the
Ndc80 complex [2–4] (Figure 1A). The first of these is
routed through the Mis12 complex, which connects to the
centromere protein CENP-C that in turn connects to histone
H3 or the histone H3 variant CENP-A embedded within
nucleosomes at the centromere [5]. The latter is mediated via
CENP-T, which forms a complex with CENP-W, CENPS and CENP-X, and, as discussed below, may also interact
directly with centromeric DNA [3,4,6]. In addition there are
a further 11 proteins (CENP-H, CENP-I, CENP-K, CENPL, CENP-M, CENP-N, CENP-O, CENP-P, CENP-Q,
CENP-U and CENP-R) that were found to associate
with CENP-A chromatin in human cells and contribute to
Key words: CENP-S/MHF1, CENP-X/MHF2, centromere, FANCM/Fml1, homologous recombination, kinetochore.
Abbreviations used: CCAN; constitutive centromere-associated network; CENP, centromere
protein; CO; crossover; D-loop; displacement loop; DSB; double-strand break; FA; Fanconi’s
anaemia; FANCM, Fanconi’s anaemia complementation group M; HJ; Holliday junction; HR;
homologous recombination; MHF; FANCM-associated histone-fold protein; NCO; non-crossover.
1
To whom correspondence should be addressed (email [email protected]).
C The
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Authors Journal compilation proper centromere and kinetochore function [1]. Together
with CENP-A, CENP-C, CENP-S, CENP-T, CENP-W
and CENP-X, these proteins form the so-called CCAN
(constitutive centromere-associated network). Importantly,
the majority of the components that make up the CCAN
appear to be conserved in yeast and humans [7].
CENP-T, CENP-W, CENP-S and CENP-X
CENP-T, CENP-W, CENP-S and CENP-X each contain
histone-fold domains, and recent structural studies have
revealed how they mediate dimerization between CENPT and CENP-W and CENP-S and CENP-X respectively
[6,8]. Moreover, in chicken and humans, these two different
heterodimers associate via regions within CENP-T and
CENP-S to form a heterotetramer that is similar in overall
structure to the heterotetramer formed by histone H3 and H4
[6]. The histone H3–H4 heterotetramer can form a tetrasome
with 80 bp of DNA wrapped around it, and as CENP-TW-S-X can introduce supercoils into DNA and protect a
100 bp region from micrococcal nuclease digestion in vitro,
it would seem that it too can form a tetrasome [6]. This
ability, if replicated in vivo, would enable CENP-T-W-SX to provide a second point of anchorage for the outer
kinetochore additional to CENP-A-containing nucleosomes
(Figure 1A). Attachment is mediated by the N-terminal
domain of CENP-T, which extends as a long tail from
its histone-fold and contacts the Spc24-25 domain of the
Ndc80 complex via a conserved peptide motif [2–4]. This
interaction is regulated by cyclin-dependent-kinase-mediated
phosphorylation of CENP-T, which enhances it in late G2 phase, ensuring that the Ndc80 complex is recruited to
kinetochores in time for mitosis [2,3,9]. The important role
that CENP-T plays in forging a functional kinetochore is
highlighted by its ability when fused to the Tet/Lac repressor
to single-handedly recruit Ndc80 to tetO/lacO arrays and, in
so doing, promote chromosome segregation [4,10,11].
Biochem. Soc. Trans. (2013) 41, 1726–1730; doi:10.1042/BST20130200
The 7th International Fission Yeast Meeting: Pombe2013
Figure 1 The cellular roles of CENP-S and CENP-X
(A) Cartoon depicting how the CENP-T-W-S-X complex forms a link
between centromeric DNA and the components of the outer kinetochore.
Adapted from Cell, 148(4), Daniel R. Foltz, P. Todd Stukenberg, A New
Histone at the Centromere?, 394–396, Copyright (2012), with permission
from Elsevier [50]. (B) Cartoon depicting a CENP-S-X heterotetramer
aiding FANCM in promoting the reversal of a stalled replication fork. (C)
Cartoon depicting a CENP-S-X heterotetramer aiding FANCM in promoting
D-loop dissociation.
Under normal conditions CENP-T depends on its
heterodimerization with CENP-W to properly associate with
kinetochores; however, surprisingly, at least in chicken and
budding yeast, CENP-S is not required [4,6,7]. In contrast,
the localization of CENP-S and CENP-X to centromeres
depends wholly on the interaction between CENP-T and
CENP-S [6]. Although CENP-T–CENP-W may be able
to localize to centromeres without CENP-S–CENP-X, the
importance of the heterotetramer is evident from studies in
human and chicken cells showing that CENP-S deficiency
causes reduced localization of Ndc80 to the outer kinetochore
and an increase in its distance from CENP-T, as well as defects
in mitotic progression and chromosome segregation [12].
Moreover, heterotetramerization of these proteins appears to
be widely conserved as their putative homologues in fission
yeast co-purify from an Escherichia coli expression system
and gel filter as a single complex with an estimated molecular
mass consistent with a heterotetrameric conformation (C.
Bryer, R. Barton and M. Whitby, unpublished work).
CENP-S and CENP-X, also known as MHF1
and MHF2
CENP-S and CENP-X, although originally identified
as centromeric proteins, were also found to co-purify
from human cells with the FANCM (Fanconi’s anaemia
complementation group M) DNA translocase resulting
in them being assigned the alternative names of MHF1
(FANCM-associated histone-fold protein 1) and MHF2
respectively [13,14]. However, for simplicity, we will continue
to refer to them as CENP-S and CENP-X. FANCM is a
component of a DNA-repair network in which defects can
result in the rare genetic disease FA (Fanconi’s anaemia) that
is characterized by progressive bone marrow failure, various
developmental abnormalities, increased cancer incidence
and cellular hypersensitivity to DNA interstrand crosslinking agents such as cisplatin and mitomycin-C. A key
role for FANCM in this network is to recruit the socalled FA core complex (composed of FANCA, FANCB,
FANCC, FANCE, FANCF, FANCG, FANCL, FAAP24
and FAAP100) to stalled replication forks, which facilitates
the monoubiquitination of FANCD2 and FANCI that then
co-ordinate downstream repair processes [15–19].
FANCM also has roles that are independent of the FA core
complex and an appreciation of what these are (or might be)
has been gained in part from studies of its yeast orthologues
(Fml1 in fission yeast and Mph1 in budding yeast), which
operate in an environment from where most other FA
proteins are absent [20]. In particular two prominent roles
in HR (homologous recombination) have been proposed
on the basis of the combined findings of biochemical and
genetic experiments: (i) promoting recombination-dependent
replication restart (Figure 1B); and (ii) promoting CO
(crossover) avoidance during DNA DSB (double-strand
break) repair (Figure 1C). The first of these roles is thought
to be achieved by an ability to catalyse the reversal of stalled
replication forks, which generates a substrate from which HR
can be initiated [21] (Figure 1B). The key data that support
this model include: (i) the ability of FANCM/Fml1/Mph1 to
catalyse the ATPase-dependent reversal of model replication
forks in vitro [22–25]; (ii) the reduction in HR induced by
replication fork blockage at the RTS1 barrier in fission yeast
when fml1 is deleted or mutated to confer ATPase deficiency
[23,24]; and (iii) the requirement for FANCM to promote
both the stabilization and restart of stalled replication forks
in mammalian cells [26].
FANCM’s second role in HR has mainly been inferred
from studies of its yeast and plant orthologues, which
reveal a prominent role in CO avoidance during DSB
repair in mitotic and/or meiotic cells [23,24,27–29]. This role
is probably conserved in vertebrates as both mammalian
and chicken DT40 cells deficient in FANCM exhibit
increased spontaneous and interstrand cross-link-induced
sister chromatid exchange [30–32]. COs are a class of
recombinant DNA that classically arise as a consequence
of the endonucleolytic resolution of HJ (Holliday junction)
intermediates resulting in the reciprocal exchange of DNA
between the recombining molecules [33]. During meiosis
COs promote the formation of chiasmata that are needed
to guide correct chromosome segregation during the first
meiotic division [34]; however, in mitotic cells, they can
result in deleterious genome rearrangements if recombination
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Biochemical Society Transactions (2013) Volume 41, part 6
occurs between ectopic homologous sequences [35]. Both
Fml1 and Mph1 have been shown to catalyse the dissociation
of D (displacement)-loops in vitro [24,28,29]. In vivo, Dloops are formed by strand invasion catalysed by the central
recombinase Rad51 and are a precursor of HJs. Through
their ability to dissociate D-loops, Fml1 and Mph1 offer an
alternative to HJ resolution (and therefore CO formation) by
driving repair down a pathway known as SDSA (synthesisdependent strand annealing), which generates only NCO
(non-crossover) recombinants (Figure 1C) [24,28,29].
The interaction between FANCM and CENP-S–CENPX is important for both the promotion of FANCD2
monoubiquitination and the suppression of spontaneous
sister chromatid exchange [13,14]. Similarly, in fission yeast,
CENP-S and CENP-X work together with Fml1 to promote
HR at blocked replication forks and NCO formation
during DSB repair in both mitotic and meiotic cells [14,28].
Biochemical and structural studies have provided some
insight into the mechanism by which CENP-S–CENP-X
contributes to FANCM/Fml1’s various roles. First, in the
absence of CENP-T–CENP-W, two heterodimers of CENPS–CENP-X associate as a tetramer, which can then interact
with a region just on the C-terminal side of FANCM’s
helicase domain [14,36]. An X-ray crystal structure of
this C-terminal domain binding to the CENP-S–CENP-X
tetramer shows that the interaction, although not causing an
allosteric change, does alter the electrostatic surface potential
of the CENP-S–CENP-X tetramer enlarging a region of
electropositive charge that probably interacts with DNA
[36]. Indeed, CENP-S–CENP-X’s ability to bind doublestranded DNA is synergistically enhanced upon interaction
with FANCM’s C-terminal domain [14,36]. This property
may explain how CENP-S–CENP-X is able to stimulate
the fork reversal activity of FANCM in vitro [13,14], and
presumably also aids substrate targeting in vivo. Certainly
mutations in Fml1 that disrupt its interaction with CENPS–CENP-X result in a reduction in CENP-S recruitment
to non-centromeric chromatin, as well as deficient DNA
repair, replication fork block-induced recombination and CO
avoidance [37].
Is FANCM/Fml1 needed at centromeres beyond
its normal roles in DNA repair?
It is clear that CENP-S–CENP-X is crucial for
FANCM/Fml1’s ability to promote DNA repair and recombination, but is the reverse true, i.e. does FANCM/Fml1
support CENP-S–CENP-X in promoting centromeric
function? A recent hypothesis postulates the intriguing idea
that recombinases may play a role in establishing an active
centromeric structure by catalysing HR between the repeated
DNA elements that are a feature of so-called regional
centromeres found in many eukaryotes including fission
yeast and humans [38]. Inter-repeat recombination has the
potential of forming a covalently closed circle of DNA
maintained via a HJ in its ‘stem–loop’. Such circles could help
to direct the assembly of CENP-A-containing nucleosomes,
and in this regard it is interesting to note that CENP-A’s
C The
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Authors Journal compilation chaperone in mammals, HJURP, is an HJ-binding protein
[38,39]. It was also speculated that tRNA genes, embedded
within fission yeast centromeres, could be the initiating sites
for HR in this organism based on their known ability to
stall replication forks [38]. Fml1 is a prime candidate for
driving this recombination through its ability to catalyse
fork reversal [23,24]. However, so far, we have found little
evidence that loss of Fml1 results in centromere dysfunction
[37]. In contrast, deletion of the genes encoding CENP-S and
CENP-X in fission yeast results in a marked reduction in
cell viability, which is associated with a high frequency of
defective chromosome segregation [37].
The importance of CO control at
centromeres
Although HR may play a role in helping to establish a fully
functional centromere, there is also evidence indicating that
its use at these sites is carefully governed and if possible
avoided. This is especially true in regional centromeres
due to the presence of repeated DNA elements and the
dangers associated with recombining them (see above). For
example, inter-chromatid recombination between inverted
repeat sequences found at fission yeast centromeres can result
in isochromosome formation [40,41], and intra-chromatid
recombination within the large arrays of directly orientated
α-satellite repeats that make up human centromeres can
result in deletions [38]. Such deletions could accrue over
time and may account for the age-related centromere ‘loss’
observed in women [42]. Moreover, it has been suggested
that centromere shortening might compromise kinetochore
assembly/function resulting in higher rates of aneuploidy
and/or a failure of cellular proliferation due to persistent
activation of the mitotic spindle checkpoint [38].
The inherent risk of using HR at regional centromeres
possibly explains why there are mechanisms in place to avoid
the need for its deployment. Included in this is machinery
that establishes heterochromatin within centromeric DNA,
which can block DSB formation during meiosis and aid
replication fork progression by displacing RNA polymerase
II from DNA [43–45], as well as factors that protect stalled
replication forks from collapsing and therefore requiring
HR to promote their restart [46,47]. However, once HR is
engaged, as a consequence of replication fork collapse or
DSB formation, it appears that, at least in maize, crossing
over is suppressed [48]. The ability of Fml1, and presumably
FANCM, to dissociate D-loops makes them prime candidates
for directing NCO recombination at centromeres. Indeed, it
is conceivable that the association between FANCM/Fml1
and CENP-S–CENP-X evolved from a need to concentrate
its activity at these chromosomal sites. Consistent with this
view it has been shown that FANCM localizes to centromeres
in a CENP-S-dependent manner in human cells [36].
Conclusion
In the present review we have summarized data showing
that CENP-S and CENP-X have a dual life in the cell,
The 7th International Fission Yeast Meeting: Pombe2013
working both at the centromere to aid kinetochore function
and more widely across the genome to promote DNA
repair and recombination. Intriguingly, they are not the
only CCAN proteins that moonlight in another aspect of
chromosome biology. In Xenopus, mouse and human cells,
CENP-A, together with at least three other CCAN proteins
(CENP-N, CENP-T and CENP-U), is recruited to sites of
non-centromeric DNA damage including DSBs, where they
are found alongside key DNA-damage-response proteins,
including RAD51, 53BP1 (p53-binding protein 1), NBS1
(Nijmegen breakage syndrome 1), ATM (ataxia telangiectasia
mutated) and CHK2 (checkpoint kinase 2) [49]. Moreover,
the loss of CENP-A from these sites was found to coincide
with the completion of DNA repair. Interestingly, the
recruitment of CENP-A to DSBs depends on its centromeretargeting domain, suggesting that it assembles at these sites
in the same way as it does at centromeres [49]. In this regard
it is also interesting to note that its chaperone HJURP is
another protein that appears to localize to DSBs and plays a
role in HR [39]. Exactly what CENP-A and its fellow CCAN
proteins are doing at sites of DNA damage and whether there
is any involvement with FANCM and CENP-S–CENP-X
is unknown. Answering these questions is an important goal
for future research.
Funding
Work in our laboratory is funded by the Wellcome Trust [grant
number 090767/Z/09/Z].
References
1 Verdaasdonk, J.S. and Bloom, K. (2011) Centromeres: unique chromatin
structures that drive chromosome segregation. Nat. Rev. Mol. Cell Biol.
12, 320–332
2 Malvezzi, F., Litos, G., Schleiffer, A., Heuck, A., Mechtler, K., Clausen, T.
and Westermann, S. (2013) A structural basis for kinetochore
recruitment of the Ndc80 complex via two distinct centromere
receptors. EMBO J. 32, 409–423
3 Nishino, T., Rago, F., Hori, T., Tomii, K., Cheeseman, I.M. and Fukagawa,
T. (2013) CENP-T provides a structural platform for outer kinetochore
assembly. EMBO J. 32, 424–436
4 Schleiffer, A., Maier, M., Litos, G., Lampert, F., Hornung, P., Mechtler, K.
and Westermann, S. (2012) CENP-T proteins are conserved centromere
receptors of the Ndc80 complex. Nat. Cell Biol. 14, 604–613
5 Screpanti, E., De Antoni, A., Alushin, G.M., Petrovic, A., Melis, T., Nogales,
E. and Musacchio, A. (2011) Direct binding of Cenp-C to the Mis12
complex joins the inner and outer kinetochore. Curr. Biol. 21, 391–398
6 Nishino, T., Takeuchi, K., Gascoigne, K.E., Suzuki, A., Hori, T., Oyama, T.,
Morikawa, K., Cheeseman, I.M. and Fukagawa, T. (2012) CENP-T-W-S-X
forms a unique centromeric chromatin structure with a histone-like fold.
Cell 148, 487–501
7 Westermann, S. and Schleiffer, A. (2013) Family matters: structural and
functional conservation of centromere-associated proteins from yeast to
humans. Trends Cell Biol. 23, 260–269
8 Yang, H., Zhang, T., Tao, Y., Wu, L., Li, H.T., Zhou, J.Q., Zhong, C. and Ding,
J. (2012) Saccharomyces cerevisiae MHF complex structurally resembles
the histones (H3-H4)2 heterotetramer and functions as a
heterotetramer. Structure 20, 364–370
9 Gascoigne, K.E. and Cheeseman, I.M. (2013) CDK-dependent
phosphorylation and nuclear exclusion coordinately control kinetochore
assembly state. J. Cell Biol. 201, 23–32
10 Gascoigne, K.E., Takeuchi, K., Suzuki, A., Hori, T., Fukagawa, T. and
Cheeseman, I.M. (2011) Induced ectopic kinetochore assembly bypasses
the requirement for CENP-A nucleosomes. Cell 145, 410–422
11 Hori, T., Shang, W.H., Takeuchi, K. and Fukagawa, T. (2013) The CCAN
recruits CENP-A to the centromere and forms the structural core for
kinetochore assembly. J. Cell Biol. 200, 45–60
12 Amano, M., Suzuki, A., Hori, T., Backer, C., Okawa, K., Cheeseman, I.M.
and Fukagawa, T. (2009) The CENP-S complex is essential for the stable
assembly of outer kinetochore structure. J. Cell Biol. 186, 173–182
13 Singh, T.R., Saro, D., Ali, A.M., Zheng, X.F., Du, C.H., Killen, M.W.,
Sachpatzidis, A., Wahengbam, K., Pierce, A.J., Xiong, Y. et al. (2010)
MHF1-MHF2, a histone-fold-containing protein complex, participates in
the Fanconi anemia pathway via FANCM. Mol. Cell 37, 879–886
14 Yan, Z., Delannoy, M., Ling, C., Daee, D., Osman, F., Muniandy, P.A.,
Shen, X., Oostra, A.B., Du, H., Steltenpool, J. et al. (2010) A histone-fold
complex and FANCM form a conserved DNA-remodeling complex to
maintain genome stability. Mol. Cell 37, 865–878
15 Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A.R., Laghmani,
el H., Joenje, H., McDonald, N., de Winter, J.P. et al. (2007) Identification
of FAAP24, a Fanconi anemia core complex protein that interacts with
FANCM. Mol. Cell 25, 331–343
16 Kim, J.M., Kee, Y., Gurtan, A. and D’Andrea, A.D. (2008) Cell
cycle-dependent chromatin loading of the Fanconi anemia core complex
by FANCM/FAAP24. Blood 111, 5215–5222
17 Meetei, A.R., Medhurst, A.L., Ling, C., Xue, Y., Singh, T.R., Bier, P.,
Steltenpool, J., Stone, S., Dokal, I., Mathew, C.G. et al. (2005) A human
ortholog of archaeal DNA repair protein Hef is defective in Fanconi
anemia complementation group M. Nat. Genet. 37, 958–963
18 Singh, T.R., Bakker, S.T., Agarwal, S., Jansen, M., Grassman, E., Godthelp,
B.C., Ali, A.M., Du, C.H., Rooimans, M.A., Fan, Q. et al. (2009) Impaired
FANCD2 monoubiquitination and hypersensitivity to camptothecin
uniquely characterize Fanconi anemia complementation group M. Blood
114, 174–180
19 Wang, W. (2007) Emergence of a DNA-damage response network
consisting of Fanconi anaemia and BRCA proteins. Nat. Rev. Genet. 8,
735–748
20 Whitby, M.C. (2010) The FANCM family of DNA helicases/translocases.
DNA Repair 9, 224–236
21 McGlynn, P. and Lloyd, R.G. (2002) Recombinational repair and restart of
damaged replication forks. Nat. Rev. Mol. Cell Biol. 3, 859–870
22 Gari, K., Decaillet, C., Delannoy, M., Wu, L. and Constantinou, A. (2008)
Remodeling of DNA replication structures by the branch point
translocase FANCM. Proc. Natl. Acad. Sci. U.S.A. 105, 16107–16112
23 Nandi, S. and Whitby, M.C. (2012) The ATPase activity of Fml1 is
essential for its roles in homologous recombination and DNA repair.
Nucleic Acids Res. 40, 9584–9595
24 Sun, W., Nandi, S., Osman, F., Ahn, J.S., Jakovleska, J., Lorenz, A. and
Whitby, M.C. (2008) The fission yeast FANCM ortholog Fml1 promotes
recombination at stalled replication forks and limits crossing over during
double-strand break repair. Mol. Cell 32, 118–128
25 Zheng, X.F., Prakash, R., Saro, D., Longerich, S., Niu, H. and Sung, P.
(2011) Processing of DNA structures via DNA unwinding and branch
migration by the S. cerevisiae Mph1 protein. DNA Repair 10, 1034–1043
26 Blackford, A.N., Schwab, R.A., Nieminuszczy, J., Deans, A.J., West, S.C.
and Niedzwiedz, W. (2012) The DNA translocase activity of FANCM
protects stalled replication forks. Hum. Mol. Genet. 21, 2005–2016
27 Crismani, W., Girard, C., Froger, N., Pradillo, M., Santos, J.L., Chelysheva,
L., Copenhaver, G.P., Horlow, C. and Mercier, R. (2012) FANCM limits
meiotic crossovers. Science 336, 1588–1590
28 Lorenz, A., Osman, F., Sun, W., Nandi, S., Steinacher, R. and Whitby, M.C.
(2012) The fission yeast FANCM ortholog directs non-crossover
recombination during meiosis. Science 336, 1585–1588
29 Prakash, R., Satory, D., Dray, E., Papusha, A., Scheller, J., Kramer, W.,
Krejci, L., Klein, H., Haber, J.E., Sung, P. and Ira, G. (2009) Yeast Mph1
helicase dissociates Rad51-made D-loops: implications for crossover
control in mitotic recombination. Genes Dev. 23, 67–79
30 Bakker, S.T., van de Vrugt, H.J., Rooimans, M.A., Oostra, A.B., Steltenpool,
J., Delzenne-Goette, E., van der Wal, A., van der Valk, M., Joenje, H., te
Riele, H. and de Winter, J.P. (2009) Fancm-deficient mice reveal unique
features of Fanconi anemia complementation group M. Hum. Mol.
Genet. 18, 3484–3495
31 Rosado, I.V., Niedzwiedz, W., Alpi, A.F. and Patel, K.J. (2009) The Walker B
motif in avian FANCM is required to limit sister chromatid exchanges but
is dispensable for DNA crosslink repair. Nucleic Acids Res. 37, 4360–4370
32 Wang, Y., Leung, J.W., Jiang, Y., Lowery, M.G., Do, H., Vasquez, K.M.,
Chen, J., Wang, W. and Li, L. (2013) FANCM and FAAP24 maintain
genome stability via cooperative as well as unique functions. Mol. Cell
49, 997–1009
C The
C 2013 Biochemical Society
Authors Journal compilation 1729
1730
Biochemical Society Transactions (2013) Volume 41, part 6
33 Svendsen, J.M. and Harper, J.W. (2010) GEN1/Yen1 and the SLX4
complex: solutions to the problem of Holliday junction resolution. Genes
Dev. 24, 521–536
34 Whitby, M.C. (2005) Making crossovers during meiosis. Biochem. Soc.
Trans. 33, 1451–1455
35 Lupski, J.R. and Stankiewicz, P. (2005) Genomic disorders: molecular
mechanisms for rearrangements and conveyed phenotypes. PLoS Genet.
1, e49
36 Tao, Y., Jin, C., Li, X., Qi, S., Chu, L., Niu, L., Yao, X. and Teng, M. (2012)
The structure of the FANCM-MHF complex reveals physical features for
functional assembly. Nat. Commun. 3, 782
37 Bhattacharjee, S., Osman, F., Feeney, L., Lorenz, A., Bryer, C. and Whitby,
M.C. (2013) MHF1-2/CENP-S-X performs distinct roles in centromere
metabolism and genetic recombination. Open Biol. 3, 130102
38 McFarlane, R.J. and Humphrey, T.C. (2010) A role for recombination in
centromere function. Trends Genet. 26, 209–213
39 Kato, T., Sato, N., Hayama, S., Yamabuki, T., Ito, T., Miyamoto, M., Kondo,
S., Nakamura, Y. and Daigo, Y. (2007) Activation of Holliday junction
recognizing protein involved in the chromosomal stability and
immortality of cancer cells. Cancer Res. 67, 8544–8553
40 Nakamura, K., Okamoto, A., Katou, Y., Yadani, C., Shitanda, T.,
Kaweeteerawat, C., Takahashi, T.S., Itoh, T., Shirahige, K., Masukata, H.
and Nakagawa, T. (2008) Rad51 suppresses gross chromosomal
rearrangement at centromere in Schizosaccharomyces pombe. EMBO J.
27, 3036–3046
41 Tinline-Purvis, H., Savory, A.P., Cullen, J.K., Dave, A., Moss, J., Bridge,
W.L., Marguerat, S., Bahler, J., Ragoussis, J., Mott, R. et al. (2009) Failed
gene conversion leads to extensive end processing and chromosomal
rearrangements in fission yeast. EMBO J. 28, 3400–3412
42 Nakagome, Y., Abe, T., Misawa, S., Takeshita, T. and Iinuma, K. (1984)
The “loss” of centromeres from chromosomes of aged women. Am. J.
Hum. Genet. 36, 398–404
C The
C 2013 Biochemical Society
Authors Journal compilation 43 Ellermeier, C., Higuchi, E.C., Phadnis, N., Holm, L., Geelhood, J.L., Thon, G.
and Smith, G.R. (2010) RNAi and heterochromatin repress centromeric
meiotic recombination. Proc. Natl. Acad. Sci. U.S.A. 107, 8701–8705
44 Zaratiegui, M., Castel, S.E., Irvine, D.V., Kloc, A., Ren, J., Li, F., de Castro,
E., Marin, L., Chang, A.Y., Goto, D. et al. (2011) RNAi promotes
heterochromatic silencing through replication-coupled release of RNA
Pol II. Nature 479, 135–138
45 Jaco, I., Canela, A., Vera, E. and Blasco, M.A. (2008) Centromere
mitotic recombination in mammalian cells. J. Cell Biol. 181, 885–892
46 Li, P.C., Petreaca, R.C., Jensen, A., Yuan, J.P., Green, M.D. and Forsburg,
S.L. (2013) Replication fork stability is essential for the maintenance of
centromere integrity in the absence of heterochromatin. Cell Rep. 3,
638–645
47 Lee, S.Y. and Russell, P. (2013) Brc1 links replication stress response and
centromere function. Cell Cycle 12, 1665–1671
48 Shi, J., Wolf, S.E., Burke, J.M., Presting, G.G., Ross-Ibarra, J. and Dawe, R.K.
(2010) Widespread gene conversion in centromere cores. PLoS Biol. 8,
e1000327
49 Zeitlin, S.G., Baker, N.M., Chapados, B.R., Soutoglou, E., Wang, J.Y., Berns,
M.W. and Cleveland, D.W. (2009) Double-strand DNA breaks recruit the
centromeric histone CENP-A. Proc. Natl. Acad. Sci. U.S.A. 106,
15762–15767
50 Foltz, D.R. and Stukenberg, P.T. (2012) A new histone at the
centromere? Cell 148, 394–396
Received 22 August 2013
doi:10.1042/BST20130200