MINIREVIEW
DNA mismatch repair system
Classical and fresh roles
Sung-Hoon Jun, Tae Gyun Kim and Changill Ban
Department of Chemistry and Division of Molecular & Life Science, Pohang University of Science and Technology, Korea
The mismatch repair (MMR) system is essential to all
organisms because it maintains the stability of the gen-
ome during repeated duplication. It is composed of a
few well-conserved proteins whose functions in the
postreplicative repair of mismatched DNA have been
characterized by co-ordinated genetic, biochemical and
structural approaches. Various functions, in addition
to mismatch repair during replication, have been
reported for MMR proteins such as antirecombination
activity between divergent sequences, promotion of
meiotic crossover, DNA damage surveillance and
diversification of immunoglobulins (Fig. 1). Recent
research has provided a great deal of information
about how MMR proteins are involved in these
diverse processes.
Prokaryotic mismatch repair
Essential components of the MMR system – MutS,
MutL, MutH and Uvr – were identified in Escherichia
coli through the genetic studies of mutants that showed
elevated mutation levels [1,2]. MMR reactions have
also been reconstituted with purified components in
E. coli [3], which drove extensive studies on prokaryotic
MMR systems.
MutS detects mismatches in DNA duplexes and initi-
ates the MMR machinery. A microscopic study sugges-
ted a possible mechanism for how MutS discriminates

Abbreviations
AID, activation-induced cytidine deaminase; ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3-related; Chk1, checkpoint kinase 1;
Chk2, checkpoint kinase 2; CSR, class switch recombination; LC20, MutL C-terminal 20 kDa; LN40, MutL N-terminal 40 kDa; MLH, MutL
homolog; MMR, mismatch repair; MSH, MutS homolog; PCNA, proliferating cell nuclear antigen; PMS, postmeiotic segregation; RPA,
replication protein A; RFC, replication factor C; S, switch; SHM, somatic hypermutation; V, variable.
FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS 1609
specific mismatch, MutS undergoes a conformational
change and unbends the bent DNA. Crystallographic
studies of Thermus aquaticus and E. coli MutS
complexed with mismatched DNA provided the molecu-
lar details of mismatch recognition [5–7], suggesting that
a homodimer of MutS binds asymmetrically to hetero-
duplex DNA (Fig. 2A). MutS has two functional
domains (a DNA-binding domain and an ATPase ⁄
dimerization domain) and the asymmetry in the
ATPase ⁄ dimerization domain was also reported to be
essential in the MMR process in vivo [8]. These two
domains are widely separated from each other, but
affect each other by conformational changes that are
induced by the binding of DNA or ATP [9]. This inter-
action is a key molecular mechanism for modulating the
function of the MutS protein in the MMR process. Only
two residues, both in the same subunit of MutS, take
part in the sequence-specific interaction with a mis-
matched base. One, a conserved glutamate (Glu41 in
T. aquaticus MutS and Glu38 in E. coli MutS), forms a
hydrogen bond with the mismatched base. Recently, this
hydrogen bond was suggested to induce an inhibition
of the ATPase activity of MutS, helping to form a stable
MutS–ATP–DNA intermediate of the downstream

ges may play key roles in co-ordinating the initial steps
of mismatch recognition with downstream processing
steps. A model for the intact MutL protein, which
includes a large central cavity, was suggested based on
Fig. 1. Various functions of mismatch repair
(MMR) proteins. MMR proteins are involved
in diverse genetic pathways through interac-
tions with different proteins. MMR proteins
increase replication fidelity by repairing
errors generated during replication. Prolifer-
ating cell nuclear antigen (PCNA) and replica-
tion factor C (RFC) work with MMR proteins
during mismatch repair in replication. Various
kinds of DNA damage trigger MMR protein-
dependent DNA damage responses that are
implemented through the activation of
ataxia telangiectasia mutated and Rad3-relat-
ed (ATR) and p53. Antibody diversification is
formed by mutations in immunoglobulin
genes that are introduced by MMR proteins
in conjunction with activation-induced cyti-
dine deaminase (AID) and DNA polymerase
g. In addition, MMR proteins regulate recom-
bination and promote meiotic crossover.
The functions of MMR proteins in green
boxes are discussed in this article, whereas
those in red boxes are not.
Various functions of mismatch repair proteins S H. Jun et al.
1610 FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS
the structures of the N-terminal domain (LN40) and

been well conserved during the evolutionary process
[3,23]. However, in contrast to MutS and MutL in
bacteria, which function as homodimers, in eukaryotes
MSHs and MLHs form heterodimers with multiple
proteins. Five highly conserved MSHs (MSH2 to
MSH6) are present in both yeast and mammals.
MSH1, which is present in mitochondria, exists only in
Fig. 2. Structures of MutS, MutL and MutH. (A) Crystal structure of the Thermus aquaticus MutS heteroduplex DNA complex (PDB acces-
sion code: 1EWQ). The MutS homodimer is formed by asymmetric subunits that are represented by ribbon diagrams in green and purple.
The heteroduplex DNA is a space-filling model. Two adjacent large channels with dimensions of  30 · 20 A
˚
and  40 · 20 A
˚
penetrate the
disk-like protein structure, and the latter is occupied by the heteroduplex DNA. The DNA is kinked sharply towards the major groove by
 60° at the unpaired base. Only one subunit (in purple) interacts with the unpaired base, thereby breaking the molecular twofold symmetry
of the homodimer. (B) Crystal structure of the N-terminal 40 kDa fragment (LN40) of Escherichia coli MutL complexed with ADPnP (PDB
accession code: 1B63). The structure of LN40 is homologous to that of an ATPase-containing fragment of DNA gyrase. ADPnP drives the
dimerization of LN40, and the dimer interface is well ordered and made entirely of the segments that were disordered in the apoprotein. (C)
A crystal structure of MutH (PDB accession code: 1AZO). The structure resembles a clamp, with a large cleft dividing the molecule into two
halves. Each half forms a subdomain that contains similar structural elements. The two subdomains share a hydrophobic interface and are
connected by three polypeptide linkers. The active site is located at an interface between two subdomains, and DNA binds in the cleft that
is 15–18 A
˚
wide and 12–14 A
˚
deep.
S H. Jun et al. Various functions of mismatch repair proteins
FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS 1611
yeast [24]. MSH4 and MSH5 show reproductive tis-

MLH1 ⁄ PMS2 heterodimers (each known as MutLa)
play a major role in mutation avoidance, and the other
two heterodimers of MutL homologs take part in the
repair of specific classes of mismatches [32]. The bio-
chemical activities and structure of MutL homologs
are closely related to those of prokaryotic MutL pro-
teins, especially in the N-terminal domain. The X-ray
crystallographic structure of the conserved N-terminal
40-kDa fragment of human PMS2 resembles that of
the ATPase fragment of E. coli MutL [33].
Extensive genetic studies in yeast have failed to find
orthologs of MutH and UvrD in the MMR system,
and there may be no homolog of these two proteins in
the eukaryotic genome [34]. Therefore, some diver-
gence in the MMR system from strand discrimination
and the nicking process might occur between prokary-
otes and eukaryotes. A recent increase in our know-
ledge of the eukaryotic MMR system provides some
understanding of this divergence.
In mammalian cell extracts, mismatches provoke ini-
tiation of excision at pre-existing nicks in exogenous
DNA substrates with high efficiency and specificity
[35,36]. The molecular nature of eukaryotic MMR
could be assessed using cell extract assays in vitro, and
components of the eukaryotic MMR system have been
identified with depletion and complementation assays
using cell extracts. One protein, identified in this way,
is proliferating cell nuclear antigen (PCNA). PCNA is
known to function as a processivity factor for replica-
tive polymerase, but some mutations in the PCNA

completely abolished by the inhibition of PCNA, 5¢
nick-directed excision is affected only minimally [42].
Finally, a mismatch-provoked 5¢fi3¢excision reaction
can be reconstituted in a purified system that compri-
ses only MutSa, MutLa, ExoI and replication protein
A (RPA), without PCNA, and the process is similar
to that observed in nuclear extracts [41]. RPA, the
eukaryotic single-stranded DNA-binding protein, has
been shown to enhance excision and stabilize excision
intermediates in crude fractions [43,44]. The activities
of ExoI are described below.
Genetic studies in yeast, and biochemical studies of
MMR activity in cell extracts, indicate that eukaryotes
use a mechanism similar to prokaryotes, with both
3¢fi5¢ and 5¢fi3¢ exonuclease activities for mis-
match correction [45]. ExoI, a 5¢fi3¢ exonuclease,
was found to play a role in mutation avoidance and
mismatch repair in yeast [46], and its physical inter-
action with MSH2 and MLH1 also support a role in
MMR [47]. Intriguingly, the mammalian ExoI was
reported to be involved in both 5¢- and 3¢ nick-directed
excision in extracts of mammalian cells [48], but how
ExoI can have a 3¢fi5¢ exonuclease activity was
unclear. Recent research by the Modrich group pro-
vides a plausible answer to this question [49]. They
reconstituted mismatch-provoked excision, directed by
a strand break located either 3¢ or 5¢ to the mispair, in
a defined human system using purified human proteins.
In the presence of the eukaryotic clamp loader replica-
tion factor C (RFC) and PCNA, 3¢fi5¢ excision was

complex network that responds to diverse cellular
stresses, including DNA damage [56]. Once stabilized
and activated by genotoxic stress, p53 can either acti-
vate or repress a wide array of different gene targets
by binding to their promoter regions, which in turn
can regulate cell cycle, cell death and other outcomes
[57]. The p53 homologs p63 and p73 induce p53-inde-
pendent apoptosis as well as affect trans-activation
of certain target genes by p53 [58,59]. Treatment of
human cells with methylating agents results in phos-
phorylation of p53 and induction of apoptosis, a
response that depends on the presence of functional
hMutSa and hMutLa [60]. UVB-induced apoptosis is
significantly reduced in MSH2-deficient cells, and it
correlates with decreased activation of p53, which sug-
gests that MSH2 may act upstream of p53 to induce
post-UVB apoptosis [61]. Cisplatin-caused DNA dam-
age increases the stability of p73, which induces apop-
tosis that is dependent on functional hMLH1 protein
[62]. Moreover, cisplatin stimulates the interaction
between PMS2 and p73, which is required for the acti-
vation of p73 and subsequent induction of apoptosis
[63]. PMS2 and p73 can also interact with each other,
independently of MLH1, suggesting that MMR pro-
teins have specific roles in the DNA damage response.
Taken together, these reports indicate that MMR pro-
teins may play roles in multiple steps of the DNA
damage response, as damage sensors and adaptors of
the pathways (Fig. 4).
The roles of MMR proteins in the response to DNA

interaction between MMR proteins and checkpoint
proteins also suggests direct roles for MMR proteins
in the DNA damage response. Both in vitro and in vivo
approaches show that MSH2 binds to Chk1 and Chk2
[68], that MLH1 associates with ATM [70] and that
these interactions are enhanced after treatment with a
methylating agent [68]. MSH2 protein physically inter-
acts with ATR in the damage response to DNA
methylation, and their interaction is required for the
phosphorylation of Chk1 [71]. ATR also serves as a
haploinsufficient tumor suppressor in MMR-deficient
cells, suggesting the genetic interaction of these pro-
teins [72]. Taken together, these findings suggest that
MMR proteins function early in the pathway that
leads from DNA methylating agents to G2⁄ M arrest
(Fig. 4).
The molecular mechanism of the involvement of
MMR proteins in various DNA damage responses
is unclear. Given the original function of the MMR
system in detecting and repairing errors that occur
during replication, the MMR protein complex could
serve as a sensor for DNA damage [71]. A large com-
plex, named BRCA1-associated genome surveillance
complex, which includes tumor suppressors and the
MMR ⁄ DNA damage-repair proteins MSH2, MSH6,
MLH1, ATM, Bloom’s syndrome, and RAD50–
MRE11–NBS1, has also been suggested to be a poss-
ible sensor for DNA damage [73]. The roles of MMR
proteins in the DNA damage response may not be
simple from the viewpoint of their various relation-

damage response, and postmeiotic segregation 2 (PMS2) is known
to bind and stabilize p73. The p38 mitogen-activated protein (MAP)
kinase pathway connects MMR proteins and p53 ⁄ p73 in this
pathway. c-Abl is a tyrosine kinase that acts upstream of p73 and
stabilizes it [59].
Various functions of mismatch repair proteins S H. Jun et al.
1614 FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS
genes and CSR is a region-specific intrachromosomal
recombination that replaces the Cl form of the immu-
noglobulin (Ig) heavy chain constant region (C
H
) gene
with other C
H
genes, resulting in a switch of the Ig iso-
type from IgM to IgG, IgE, or IgA [77]. The mole-
cular processes of SHM and CSR, and the proteins
involved in these processes, have been investigated in
detail over the last few years. Advances in gene target-
ing techniques have led to the availability of mice with
loss-of-function mutations in MMR genes, and recent
studies using these mice have suggested that MMR
proteins are directly involved in antibody diversifica-
tion. MSH2-deficient mice accumulated fivefold fewer
mutations in the V region of antibody genes [78].
MSH6 deficiency caused similar effects, but MSH3
deficiency did not [79], suggesting that MutSa plays an
essential role in SHM. Similarly, mice with loss-
of-function mutations in MSH2 or MSH6 have a
decreased frequency of CSR, but those with MSH3

such as pol g (Fig. 5) [87]. This model is supported
by a report that MSH a not only binds to a U:G
mispair, but also physically interacts with DNA poly-
merase g and functionally stimulates its catalytic
activity [88]. Moreover, the phenotypes of mice
mutant for ExoI are similar to those of MSH2– ⁄ –
mice, with reduced SHM and CSR, and ExoI and
MLH1 physically interact with mutating variable
regions [89].
A
B
C
D
Fig. 5. A model of somatic hypermutation that is dependent on the mismatch repair (MMR) protein. (A) During transcription of the immuno-
globulin gene in the variable (V) region, activation-induced cytidine deaminase (AID) deaminates cytidine residues in single-stranded DNA to
produce UG mismatches. (B) MutSa and MutLa are recruited to the mismatched DNA, and activate ExoI. (C) The gaps generated by the
activity of ExoI are refilled by error-prone DNA polymerase g, resulting in mutations in AT base pairs. (D) The diversity of the V regions of
antibody genes is thus accomplished by the formation of mutations by a mechanism that depends on MMR proteins.
S H. Jun et al. Various functions of mismatch repair proteins
FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS 1615
Conclusion
The MMR system was originally discovered as a
mechanism that maintains the integrity of the genome
during replication. Increasingly, however, components
of the system are being found to participate in diverse
cellular processes, including the repair of DNA dam-
age and antibody diversification. How MMR proteins
are regulated to perform these various functions will
be an important question for the co-ordinated under-
standing of MMR proteins. Searching for the unidenti-

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