[Cell Cycle 6:8, 914-918, 15 April 2007]; ©2007 Landes Bioscience
Perspective
SMC Proteins, New Players in the Maintenance of Genomic Stability
Felipe Cortés-Ledesma1
Giaccomo de Piccoli2
James E. Haber3
Luis Aragón2
Andrés Aguilera1,*
2MRC Clinical Sciences Centre; Imperial College London; London, UK
3Rosenstiel Center; Brandeis University; Waltham, Massachusetts USA
*Correspondence to: Andrés Aguilera; Department of Molecular Biology;
CABIMER, CSIC-Universidad de Sevilla; Av. Americo Vespucio s/n; 41092 Sevilla,
Spain; Tel.: +34.954.468.372; Fax: +34.954.461.664; Email: [email protected]
Mitotic homologous recombination (HR) is one of the main mechanisms responsible
for the repair of DNA double‑strand breaks (DSBs),1 including those that occur during
DNA replication.2‑5 Therefore HR is crucial to maintain the integrity of the genetic material. The process involves repair of damaged DNA using a homologous DNA sequence as
template. This makes HR an accurate process unlike the alternative DSB repair mechanism,
nonhomologous end joining (NHEJ), which does not use additional DNA molecules.6
Thus, HR results in the transfer of information to the damaged DNA molecule (gene
conversion) that may or may not be associated with a reciprocal exchange (crossover).
Paradoxically, crossover‑associated HR can also be a source of genome rearrangements
depending on the DNA template used. Indeed, increased HR it is often associated with
genome instability.7 Therefore, HR is a double‑edged sword that must be tightly regulated
to ensure that DNA lesions are repaired in a way that does not compromise the integrity of
the genome. Consistent with this view, crossover suppression mechanisms exist from yeast
to higher eukaryotes8,9 explaining why crossovers are rare events during mitosis.1,10
An important element determining the outcome of HR is the DNA molecule chosen as
donor of information. This, known as “partner choice”, is an important step in the control
of recombination and key in preventing the deleterious consequences of recombination.
In diploids undergoing meiosis, the most common donor for HR is the homologous
chromosome. However, in mitosis this inter‑allelic recombination can result in loss of
heterozygosity, an event frequently associated with tumorigenesis.11 Recombination
between homologous DNA repeats located elsewhere in the genome (ectopic recombination) can also result in loss or reorganization of the genetic material.
Another possible donor of information for the repair of DSBs by HR is the identical
sequence located on the replicated sister chromatid (sister chromatid recombination,
SCR). Even if there is crossing‑over associated with repair, SCR results in error‑free repair
and it appears to be the preferred HR repair pathway in yeast and mammalian cells.12‑14
Moreover, the proximity of sister chromatids during replication, a process thought to be
the main source of spontaneous DNA damage,15 makes SCR an ideal repair pathway. In
this regard it is worth noting that HR is more active during the stages of the cell cycle in
which the sister chromatid is present, namely the S and G2 phases.16‑19
Despite the importance of SCR in safeguarding genome integrity, the molecular
mechanisms driving the bias towards the sister chromatid as the donor molecule during
recombination are poorly understood. This is in part due to the difficulty in the detection of SCR products and the fact that HR studies have traditionally been focused on
allelic and ectopic recombination systems. However, some assays for the study of SCR
have been developed20 and their use has revealed that the dependency of SCR on the
main HR genes is similar to that observed for allelic and ectopic recombination.12,14,21‑26
This demonstrates that HR has common gene requirements regardless of the donor used
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Original manuscript submitted: 02/28/07
Manuscript accepted: 03/02/07
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of Molecular Biology; CABIMER, CSIC-Universidad de Sevilla;
Sevilla, Spain
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Homologous recombination (HR) is one of the key mechanisms responsible for the
repair of DNA double‑strand breaks (DSBs), including those that occur during DNA repli‑
cation. Recent studies in yeast and mammals have uncovered that the SMC complexes
cohesins and Smc5‑Smc6 are recruited to induced DSBs, and play a role in the mainte‑
nance of genome stability by favouring SCR as the main recombinational DSB repair
mechanism. These new results raise intriguing questions such as whether SMC proteins
might play a functional role at collapsed replication forks, which may represent the main
source of spontaneous recombinogenic damage. A deeper knowledge of the role of
SMC proteins in DSB repair should contribute to a better understanding of chromosome
dynamics and stability.
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Previously published online as a Cell Cycle E-publication:
http://www.landesbioscience.com/journals/cc/abstract.php?id=4107
Key words
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sister chromatid exchange, double-strand
break repair, homologous recombination,
break-induced replication, collapsed replication forks, cohesins, MRX/MRN complex,
Smc5-Smc6, SMC complexes
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Abstract
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SMC Proteins and Genome Stability
and that the sister chromatid bias must be established independently
of bona fide HR functions. The question then arises as to how do
cells favour SCR in detriment to other forms of HR. Recent data
has demonstrated that structural protein complexes favor SCR over
other HR events, in particular complexes containing SMC (structural maintenance of chromosomes) heterodimers, like cohesin or
Smc5‑Smc6, are critical in ensuring sister chromatid bias during
mitotic recombinational repair.27‑30
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Figure 1. Schematic representation of the structure and subunit composition
for the three eukaryotic SMC complexes.
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intra‑chromatid recombination (ICR). While SCR is the major DSB
repair mechanism observed in wild‑type cells, it is very inefficient in
the thermosensitive smc3 and scc1 cohesin mutants, as well as in scc2,
which is required for cohesin loading. Interestingly, this decrease in
SCR is accompanied by an increase in ICR, demonstrating that in
the absence of functional cohesins the preference for the sister chromatid as the repair partner is lost and other homologous sequences
can become preferential templates.
Condensins. Condensin is a large multi‑protein complex that
contains an Smc2 and Smc4 heterodimer in addition to three nonSmc subunits.31 The complex plays a key role in the assembly and
condensation of mitotic chromosomes.31 In addition, condensins
have been shown to participate in DNA repair, but it remains to
be determined whether this function is related to SCR.34 Proximity
between sister chromatids can offer an advantage for SCR, providing
a link between cohesion and the preference for the sister chromatid
in double‑strand break repair. In this context, condensin has been
shown to provide cohesion, independently of cohesin, at several yeast
loci,38 thus raising the possibility that condensin, like cohesin, could
favour interactions with the sister chromatid during repair, therefore
facilitating SCR.
Smc5‑Smc6. The Smc5‑Smc6 heterodimer is at the centre of
a large essential complex constituted by six additional subunits in
budding yeast (Nse1‑6).31 In contrast to cohesin and condensin,
little is known about the precise essential function of this complex.
Mutants in all subunits of the complex are sensitive to various
DNA‑damaging agents,34 demonstrating that the Smc5‑Smc6
complex plays an important role in DNA repair. This sensitivity
is epistatic with mutations in the HR machinery and smc5‑smc6
mutants display reduced damage‑induced HR, suggesting that these
mutants have defects in recombinational repair. However, the putative function of Smc5‑Smc6 during HR remains unknown. One
possibility is that the role of the complex during recombinational
repair is not related to the HR process itself but, like cohesin, with
favouring sister chromatid interactions during the recombinational
repair process. Recent observations in yeast and human cells suggest
that this may indeed be the case.
The genome‑wide localisation of the Smc5‑Smc6 complex during
uncompromised cell cycles is similar to that of cohesin, with the
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The discovery of structural maintenance of chromosomes (SMC)
proteins, almost a decade ago, has increased our understanding of
higher order chromosome structure significantly. SMC proteins are
chromosomal ATPases, highly conserved from bacteria to humans,
that constitute the core of protein complexes involved in different
aspects of chromosome metabolism.31 SMC proteins fold back on
themselves through antiparallel coiled‑coil interactions, creating
the catalytic ATPase ‘head’ domain (at one end) by interaction
between amino and carboxy termini and, in addition, a ‘hinge’
domain (at the other). SMC heterodimers form through the association of two SMC proteins at the hinge domain thus forming a
V‑shaped molecule (Fig. 1). In SMC complexes other non-SMC
subunits associate with this structural core. In eukaryotes three SMC
complexes exist: cohesin (Smc1‑Smc3), condensin (Smc2‑Smc4)
and the Smc5‑Smc6 complex (Fig. 1). In addition, Rad50, part of
the Mre11‑Rad50‑Xrs2/Nbs1 complex (MRX in yeast, MRN in
mammals), is also an SMC‑like protein.
Cohesins. Cohesins are formed by a Smc1‑Smc3 heterodimer core
and two additional subunits, Scc1 and Scc3, that close the V‑shaped
structure by simultaneous binding of Scc1 to the globular domains
of Smc1 and Smc332 (Fig. 1). Cohesins play a mayor role in chromosome segregation because they hold sister chromatids together
(cohesion) from S phase to the onset of anaphase. It seems that this
function might be fulfilled by the entrapment of the sister chromatids inside the ring‑like structure.33 Interestingly, cohesin mutants
also display DNA repair defects. Based on the well‑established function of cohesins in sister chromatid cohesion, it has been proposed
that cohesins might be important in the repair of DNA lesions by
SCR.34 Indeed several observations are consistent with this hypothesis. Transcriptional repression of SCC1 in chicken DT40 cells
decreases SCR and increases at least 3‑fold the frequency of spontaneous and radiation‑induced chromosome aberrations.35 Molecular
analysis of protein dynamics during DSB‑repair in S. cerevisiae by
Chromatin Immunoprecipitation (ChIP) has revealed that cohesins
are loaded along a region expanding several kilobases at both sides
of the DNA break.36,37 Importantly, de novo loading of cohesins at
the break establishes cohesion between sisters and is required for the
efficient repair of an X‑ray‑irradiated chromosome but not for the
repair of the break by NHEJ or ectopic recombination.36,37 These
studies suggested that by holding the broken chromatid and its sister
together cohesins could provide a bias towards SCR during repair.
However, a direct demonstration that cohesins channel the repair of
DSBs through SCR rather than other repair pathways was lacking.
This issue has now been addressed in S. cerevisiae with a recombination assay that produces a DSB in a plasmid during replication.28
The break is generated when a DNA single‑strand break induced
at a specific site is converted into a DSB by the passage of the
replication fork.28 This assay can determine at the molecular level
the kinetics of DSB repair by SCR in competition with ectopic
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Role of SMC Proteins in Sister‑Chromatid Preference
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SMC Proteins and Genome Stability
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roles of MRX, cohesin and Smc5/6 make it difficult to know the
contributions of each to other kinds of HR������������������������������
. It is necessary to properly
define the relevance of MRX in SCR versus other kinds of HR events
to clarify this issue.
In addition to DSBs, recent observations indicate that Smc5‑Smc6
is also recruited to collapsed replication forks.27,45 The addition of
hydroxyurea (HU), which depletes the cellular dNTP pools, causes
stalling of replication forks. As a consequence, intra‑S‑phase checkpoint mechanisms are required to stabilize stalled forks, so that
these remain competent to resume replication as soon as appropriate
conditions are re-established.46 In the absence of such checkpoint
mechanisms, replication forks collapse rendering unprocessive forks
that need to be restarted in order to resume replication. In S. cerevisiae the addition of HU does not induce loading of the Smc5‑Smc6
complex onto chromatin per se, but it does in the absence of the
fork‑stabilizing checkpoint protein Rad53,27 conditions under which
replication forks collapse. This resembles the behaviour of HR foci
in S. cerevisiae, which only increase under conditions in which
replication‑forks are believed to collapse.47 Consistent with this idea,
mutants in S. pombe Smc5‑Smc6 are sensitive to HU, a defect that is
increased in the absence of Cds1 (homolog of Rad53).45 This loss in
viability motivated by HU is proposed to be due to aberrant recombination structures that are formed after replication restart in the
absence of Smc5‑Smc6, and that result in segregation defects during
mitosis. These results suggest that, the Smc5‑Smc6 complex might
be required for the proper restart of replication forks after collapse.
Indeed Smc5‑Smc6 loading during replication is observed in Xenopus
laevis extracts.48 However in this system Smc5‑Smc6 is not recruited
to DSBs.
Little is known about the mechanisms of replication‑fork restart,
but in the case of broken replication forks resulting in one‑ended
DSBs, it is generally accepted that replication can be reinitiated
by break‑induced replication (BIR). BIR is a HR mechanism that
involves the invasion of the broken arm of the replication fork on
its sister template to prime DNA synthesis and reestablish the replication fork.49,50 It is thus possible that Smc5‑Smc6 and probably
cohesins could act in this process by facilitating sister‑chromatid
BIR events. However, recent observations suggest that BIR is a very
inefficient mechanism, taking more than three hours to initiate
DNA synthesis,51 which is inconsistent with a possible role of BIR
in the rescue of collapsed replication forks. Furthermore, studies in
S. pombe suggest that replication and recombination are temporally
separated processes, which make it unlikely that collapsed replication forks are restarted by HR, despite its role in the post‑replicative
repair.52 One possibility is that SMC complexes act at collapsed replication forks by building tight interactions with the sister chromatid,
to ensure that this template is used in subsequent recombinational
repair during G2.
Finally, the role of SMC complexes in avoiding genome stability
is also evident in highly repeated regions of the genome, as is the case
of the rDNA repeats. In such regions the numerous homologous
DNA repeats, can compete with the sister chromatid as potential
repair templates. An increased instability in the rDNA repeats has
been reported for mutants in the three eukaryotic SMC complexes:
cohesins, condensins and Smc5‑Smc6.39,53‑55 Whether the control
of rDNA stability by SMC proteins is governed by the same
mechanisms as in other regions of the genome is a question yet to
be deciphered.
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ribosomal gene array (rDNA), telomeres and centromeres as the
main binding sites.27,39 In addition, binding of the complex at intergenic regions of the genome has also been observed.27 Interestingly,
when a DSB is induced at a defined position in the genome,
Smc5‑Smc6 subunits are recruited to the vicinity of the break and
become enriched within a region that covers several kilobases around
the break, a similar binding‑pattern to that shown for cohesins.27,29
These findings are in agreement with a role of this complex in DSB
repair. Consistently, smc6 mutants are defective in the recovery
of a full‑length chromosome after g‑irradiation.27 Furthermore,
smc6 mutant cells are not deficient in NHEJ,29 which, together
with the fact that the DSB‑dependent enrichment of Smc5‑Smc6
is specially observed in G2/M cells,27,29 strongly supports the idea
that the DSB‑repair role of the complex is related to HR. However,
mating‑type switching, an ectopic recombination event that depends
on the HR machinery is not affected in the absence of functional
Smc6 or Nse3 proteins,29 suggesting that the repair defect observed
is not due to a general HR deficiency. All these phenotypes suggest
that the Smc5‑Smc6 complex, like cohesin, could be specifically
required for SCR.
Analysis of SCR in smc5‑smc6 mutants using the same recombination assay described earlier for cohesin has revealed that the
Smc5‑Smc6 complex is also required for efficient repair of DSB by
SCR.29 In addition, smc5‑smc6 mutants suffer from higher levels
of gross chromosomal rearrangements (GCRs).29 Interestingly, the
increase in GCRs in the mutants is suppressed if Rad51 is deleted,
indicating that GCRs occur by an HR‑dependent mechanism.
Taken together these results strongly suggest that the presence of
Smc5‑Smc6 favours repair by SCR, and in its absence HR using a
donor other than the sister is more likely to occur, thus resulting in
genomic instability.
The role of Smc5‑Smc6 in SCR is evolutionary conserved. The
study of the role of the Smc5‑Smc6 complex in SCR compared to
other types of DSB repair has been also performed in human cells.30
RNAi‑mediated knock down of Smc5‑Smc6 components decreases
SCR, as determined cytologically and genetically, while it does not
affect NHEJ or other types of HR, some of which are even increased,
consistent with the results obtained in yeast. In addition, the
Smc5‑Smc6 complex is required to repair DNA damage during late
S and G2, but not G1. Thus Smc5‑Smc6 is important for DNA repair
in the cell cycle stages where the sister chromatid is present. Although
this is consistent with a role in SCR, a general role in HR cannot be
excluded, since HR is notably more active during S and G2.
Recent work has shown that the human Smc5‑Smc6 complex is
also recruited to induced DSBs. Furthermore, the loading of human
cohesin to DSB depends on Smc5‑Smc6, suggesting that, at least in
part, the SCR defect in smc5‑smc6 mutants is mediated by lack of
cohesin recruitment,30 thus both SMC complexes act in the same
pathway to promote SCR. This view was further supported by the
fact that the defect in SCR is epistatic when both complexes are
knocked down.30
In budding yeast, recruitment of both cohesin and Smc5/6
complexes proves to be dependent on the MRX complex, which
includes the SMC‑like Rad50 protein. Early studies showed that
Rad50 and Xrs2 deletions cause a slight increase in spontaneous interhomolog allelic recombination.40‑42 This result could be interpreted
as indicating that the MRX complex plays a role in channelling repair
to sister chromatids and that, in its absence, repair between nonsisters
would be enhanced. Indeed a role of MRX in SCR has been observed
at both genetic and molecular levels.12,43,44 However, ���������������
the intertwined
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Several independent studies in different organisms have uncovered a role for the SMC complexes, cohesins and Smc5‑Smc6
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Deciphering the complex interplay of SMC proteins in repair by SCR
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