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Key words The molecular mechanisms of the DNA mismatch repair (MMR) system
antibody diversification; DNA damage have been uncovered over the last decade, especially in prokaryotes. The
response; DNA mismatch repair; MutL;
results obtained for prokaryotic MMR proteins have provided a frame-
MutS
work for the study of the MMR system in eukaryotic organisms, such as
Correspondence yeast, mouse and human, because the functions of MMR proteins have
C. Ban, Department of Chemistry, Pohang been conserved during evolution from bacteria to humans. However, muta-
University of Science and Technology, tions in eukaryotic MMR genes result in pleiotropic phenotypes in addition
Pohang 790–784, Korea to MMR defects, suggesting that eukaryotic MMR proteins have evolved
Fax: +82 54 2793399 to gain more diverse and specific roles in multicellular organisms. Here, we
Tel: +82 54 2792127
summarize recent advances in the understanding of both prokaryotic and
E-mail: ciban@postech.ac.kr
eukaryotic MMR systems and describe various new functions of MMR
(Received 12 December 2005, accepted proteins that have been intensively researched during the last few years,
10 February 2006) including DNA damage surveillance and diversification of antibodies.
doi:10.1111/j.1742-4658.2006.05190.x
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
Various functions of mismatch repair proteins S.-H. Jun et al.
specific mismatch, MutS undergoes a conformational interactions and hydrogen bonds between the DNA
change and unbends the bent DNA. Crystallographic backbone and side chains of MutS are sequence inde-
studies of Thermus aquaticus and E. coli MutS pendent [5,6]. After the recognition of mismatched
complexed with mismatched DNA provided the molecu- DNA, MutS initiates the MMR system through direct
lar details of mismatch recognition [5–7], suggesting that or indirect interactions with other proteins, including
a homodimer of MutS binds asymmetrically to hetero- MutL, MutH and UvrD. Although an exact answer to
duplex DNA (Fig. 2A). MutS has two functional this puzzle is yet to be found, a few groups have sugges-
domains (a DNA-binding domain and an ATPase ⁄ ted various models for detailed molecular events during
dimerization domain) and the asymmetry in the MMR reactions (Fig. 3) [11].
ATPase ⁄ dimerization domain was also reported to be The function of MutL in the MMR system is to
essential in the MMR process in vivo [8]. These two make a connection between the recognition of a mis-
domains are widely separated from each other, but match and the excision of the mismatch from the
affect each other by conformational changes that are strand within which it is contained [12]. To do this, a
induced by the binding of DNA or ATP [9]. This inter- MutL homodimer interacts with MutS [13] and stimu-
action is a key molecular mechanism for modulating the lates the endonuclease activity of MutH [14]. MutL
function of the MutS protein in the MMR process. Only also loads UvrD onto the DNA. UvrD is a DNA
two residues, both in the same subunit of MutS, take helicase II that unwinds the DNA duplex from the
part in the sequence-specific interaction with a mis- nick generated by MutH [15,16]. MutL is a member of
matched base. One, a conserved glutamate (Glu41 in the GHKL superfamily of ATPases, which includes gy-
T. aquaticus MutS and Glu38 in E. coli MutS), forms a rase, a type II topoisomerase, Hsp90, histidine kinase
hydrogen bond with the mismatched base. Recently, this and MutL [17]. A biochemical study demonstrated that
hydrogen bond was suggested to induce an inhibition MutL has ATPase activity [17,18]. Crystallographic
of the ATPase activity of MutS, helping to form a stable studies have demonstrated that ATP binding drives
MutS–ATP–DNA intermediate of the downstream dimerization of the N-terminal domain of the protein
repair process [10]. The other specific interaction is (Fig. 2B) [18], and the accompanying structural chan-
between an aromatic ring stack of a conserved phenyl- ges may play key roles in co-ordinating the initial steps
alanine (Phe39 in T. aquaticus MutS and Phe36 in of mismatch recognition with downstream processing
E. coli MutS) and the mismatched base. In contrast to steps. A model for the intact MutL protein, which
these sequence–specific interactions, van der Waals includes a large central cavity, was suggested based on
1610 FEBS Journal 273 (2006) 1609–1619 ª 2006 The Authors Journal compilation ª 2006 FEBS
S.-H. Jun et al. Various functions of mismatch repair proteins
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 Å and 40 · 20 Å 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 Å wide and 12–14 Å deep.
the structures of the N-terminal domain (LN40) and synthesized strand between the nick and the mismatch
the C-terminal domain (LC20), which were reported is carried out by four redundant single-strand DNA-
separately [17–19]. A biochemical assay, using various specific exonucleases: the 3¢ fi 5¢ exonucleases ExoI
mutant MutL proteins, suggested that LC20 is involved and ExoX and the 5¢ fi 3¢ exonucleases RecJ and
in the DNA-binding activity of MutL. An increase in ExoVII [22]. DNA polymerase III, single-stranded
the DNA-binding activity of MutL also resulted in DNA-binding protein and DNA ligase carry out repair
higher UvrD helicase activity [19]. synthesis [3].
MutH is a member of the type II family of res-
triction endonucleases and cleaves at hemimethyl-
Eukaryotic mismatch repair
ated GATC sites for excision of mismatch-containing
strands [20]. The nicking activity of MutH is stimula- All eukaryotic organisms, including yeast, mouse and
ted in a mismatch-dependent manner by MutS, MutL human, have MutS homologs (MSHs) and MutL
and ATP [20]. A structural study suggested that the homologs (MLHs). The eukaryotic MMR system has
C-terminal helix of MutH might act as a molecular been well conserved during the evolutionary process
lever through which MutS and MutL communicate [3,23]. However, in contrast to MutS and MutL in
and activate MutH (Fig. 2C) [21]. The nick generated bacteria, which function as homodimers, in eukaryotes
by MutH serves as a point of entry for single-stranded MSHs and MLHs form heterodimers with multiple
DNA-binding protein and UvrD ⁄ helicase II, whose proteins. Five highly conserved MSHs (MSH2 to
loading at the nick is facilitated via protein–protein MSH6) are present in both yeast and mammals.
interactions with MutL [15,16]. Excision of the newly MSH1, which is present in mitochondria, exists only in
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S.-H. Jun et al. Various functions of mismatch repair proteins
completely abolished by the inhibition of PCNA, 5¢ DNA damage in normal cells showed that N-methyl-
nick-directed excision is affected only minimally [42]. N¢-nitro-N-nitrosoguanidine, an alkylating agent, trig-
Finally, a mismatch-provoked 5¢ fi 3¢excision reaction gers MMR-dependent G2 ⁄ M arrest [54], which is
can be reconstituted in a purified system that compri- followed by the induction of MMR-dependent apopto-
ses only MutSa, MutLa, ExoI and replication protein sis [55].
A (RPA), without PCNA, and the process is similar The role of MMR proteins in response to DNA
to that observed in nuclear extracts [41]. RPA, the damage can be inferred from the interactions of MMR
eukaryotic single-stranded DNA-binding protein, has proteins with the tumor suppressor protein, p53, and
been shown to enhance excision and stabilize excision p53-related proteins. p53 acts as a major point in a
intermediates in crude fractions [43,44]. The activities complex network that responds to diverse cellular
of ExoI are described below. stresses, including DNA damage [56]. Once stabilized
Genetic studies in yeast, and biochemical studies of and activated by genotoxic stress, p53 can either acti-
MMR activity in cell extracts, indicate that eukaryotes vate or repress a wide array of different gene targets
use a mechanism similar to prokaryotes, with both by binding to their promoter regions, which in turn
3¢ fi 5¢ and 5¢ fi 3¢ exonuclease activities for mis- can regulate cell cycle, cell death and other outcomes
match correction [45]. ExoI, a 5¢ fi 3¢ exonuclease, [57]. The p53 homologs p63 and p73 induce p53-inde-
was found to play a role in mutation avoidance and pendent apoptosis as well as affect trans-activation
mismatch repair in yeast [46], and its physical inter- of certain target genes by p53 [58,59]. Treatment of
action with MSH2 and MLH1 also support a role in human cells with methylating agents results in phos-
MMR [47]. Intriguingly, the mammalian ExoI was phorylation of p53 and induction of apoptosis, a
reported to be involved in both 5¢- and 3¢ nick-directed response that depends on the presence of functional
excision in extracts of mammalian cells [48], but how hMutSa and hMutLa [60]. UVB-induced apoptosis is
ExoI can have a 3¢ fi 5¢ exonuclease activity was significantly reduced in MSH2-deficient cells, and it
unclear. Recent research by the Modrich group pro- correlates with decreased activation of p53, which sug-
vides a plausible answer to this question [49]. They gests that MSH2 may act upstream of p53 to induce
reconstituted mismatch-provoked excision, directed by post-UVB apoptosis [61]. Cisplatin-caused DNA dam-
a strand break located either 3¢ or 5¢ to the mispair, in age increases the stability of p73, which induces apop-
a defined human system using purified human proteins. tosis that is dependent on functional hMLH1 protein
In the presence of the eukaryotic clamp loader replica- [62]. Moreover, cisplatin stimulates the interaction
tion factor C (RFC) and PCNA, 3¢ fi 5¢ excision was between PMS2 and p73, which is required for the acti-
supported by MutSa, MutLa, ExoI and RPA. More- vation of p73 and subsequent induction of apoptosis
over, RFC and PCNA act to suppress 5¢ fi 3¢ excision [63]. PMS2 and p73 can also interact with each other,
when the strand break that directs hydrolysis is located independently of MLH1, suggesting that MMR pro-
3¢ to the mismatch, which suggests that the polarity of teins have specific roles in the DNA damage response.
mismatch-provoked excision by ExoI is regulated by Taken together, these reports indicate that MMR pro-
PCNA and RFC. Once the strand is excised beyond teins may play roles in multiple steps of the DNA
the mismatch, DNA resynthesis occurs by the activity damage response, as damage sensors and adaptors of
of polymerase d [50] in the presence of PCNA [51] and the pathways (Fig. 4).
RPA [43,44]. The remaining nick is then sealed by The roles of MMR proteins in the response to DNA
an as-yet-unidentified ligase, completing the repair damage are further supported by the failure of MMR
process. mutants to trigger G2 ⁄ M arrest in response to the
methylator N-methyl-N¢-nitro-N-nitrosoguanidine and
similar alkylators [64]. The G2 ⁄ M checkpoint prevents
MMR proteins in the DNA damage
cells from initiating mitosis when they experience
response
DNA damage during G2, or when they progress into
The involvement of MMR proteins in the DNA dam- G2 with unrepaired damage incurred during the previ-
age response first became apparent when it was discov- ous S or G1 phases [65]. A study with a cell line lack-
ered that MMR-defective bacterial and mammalian ing hMLH1 expression and an inducible hMLH1
cells are resistant to cell death caused by alkylating expression system showed that methylation-induced
agents [52]. MMR-deficient cells are also resistant to G2 ⁄ M arrest requires a full complement of hMLH1
other DNA-damaging agents, including methylation (expression level similar to that of the wild type),
agents, cisplatin and UV radiation [53]. Subsequent whereas MMR proficiency was restored, even at low
studies on the roles of MMR proteins in response to hMLH1 concentrations ( 10% of wild-type expres-
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Various functions of mismatch repair proteins S.-H. Jun et al.
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S.-H. Jun et al. Various functions of mismatch repair proteins
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.
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S.-H. Jun et al. Various functions of mismatch repair proteins
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