Hijacked DNA repair proteins and unchained DNA polymerases

Saribasak, Huseyin; Rajagopal, Deepa; Maul, Robert W.; Gearhart, Patricia J.

doi:10.1098/rstb.2008.0188

Cited by 27 publications

(25 citation statements)

References 42 publications

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“…Although the present study and previous work have shown that PMS2 plays a role in postreplicative MMR and in the repair of double-stranded DNA breaks in Ig switching regions, deficiency of the protein has a modest or no effect during SHM of the Ig locus (16)(17)(18)(19). Considering the possibility that other factors (e.g., MLH3 or apurinic/apyrimidinic endonuclease) might efficiently compensate for the absence of PMS2 and fulfill the endonucleolytic requirements of V-region hypermutation, we investigated SHM in our mutant mice.…”

Section: Resultsmentioning

confidence: 67%

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PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Oers

Roa

Werling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2 E702K knock-in mice. Pms2 EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2 EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2 −/− mice, Pms2 EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.DNA mismatch repair | B cell lymphoma | class switch recombination | somatic hypermutation | spermatogenesis P MS2 is an essential component of DNA mismatch repair (MMR) complexes, which play an important role in maintaining genetic stability. MMR functions primarily in the detection and repair of mismatched bases that result from erroneous replication, and also plays important roles in DNA damage response, genetic recombination, control of meiotic progression, and generation of antibody diversity (1). During MMR, heterodimeric MutS homolog (MSH) complexes, consisting of either MSH2 and MSH6 (MutSα) or MSH2 and MSH3 (MutSβ), bind to mismatched bases. On binding, a conformational change in the MutS complexes activates downstream events and leads to the recruitment of MutL homolog (MLH) complexes consisting of either MLH1 and PMS2 (MutLα) or MLH1 and MLH3 (MutLγ). MutLα interacts with the MutS complexes via MLH1, and this interaction is essential for the coordination of downstream repair events, including excision of the mismatch carrying strand and its resynthesis (2, 3).Important insights into the role of MutLα in MMR came from biochemical studies of reconstituted human MMR (4, 5), which showed that PMS2 is a latent endonuclease that introduces additional nicks into the discontinuous DNA strand of nicked heteroduplex substrates. This activity is dependent on the integrity of a highly conserved metal-binding motif found in many MutL homologs, including MLH3. MutLα appears to play an essential role in 3′-directed MMR, where the bias for incision on the distal side of the mismatch results in a 5′ entry site for MutSα-activated Exo1. For 5′-directed MMR, however, several studies in both the reconstituted human MMR system and MutLα-deficient cells have shown that MutLα is not essential, and that a purified system consisting of MutSα, Exo1, and RPA is sufficient to support 5′-directed MMR (6, 7). Studies in yeast have further delineated roles of the PMS2 endonuclease activity in DNA repair, recombination, and the DNA damage response (5,8,9).Pms2 −/− mice (10) showed an increase in base substitution and insertion/deletion mutation frequencies at both a reporter locus and microsatellite sequences, with a higher proportion of frameshift mutations compared with other MMR knockout models, such as...

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Section: Resultsmentioning

confidence: 67%

“…PMS2 also plays a role in class switch recombination (CSR) of Ig genes, because Pms2 −/− mice (14,15) and patients with deleterious homozygous mutations in PMS2 (16) have a significant reduction in isotype switching. Despite numerous reports (16)(17)(18)(19), however, the role of PMS2 in somatic hypermutation (SHM), if any, has not been resolved.…”

mentioning

confidence: 99%

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Oers

Roa

Werling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…This process is initiated by activationinduced cytidine deaminase (AID), which induces class switch recombination (CSR) by deaminating deoxycytidines within Ig switch regions (1,2). The recognition and subsequent processing of the mutated residues by base excision repair and/or mismatch repair machineries generates double-stranded DNA breaks (DSBs) at switch regions (3). In an attempt to mend the ensuing breaks, B cells mount a damage response similar to that signaled by irradiated cells (1).…”

mentioning

confidence: 99%

The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination

Ramachandran

Chahwan

Nepal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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An effective immune response requires B cells to produce several classes of antibodies through the process of class switch recombination (CSR). Activation-induced cytidine deaminase initiates CSR by deaminating deoxycytidines at switch regions within the Ig locus. This activity leads to double-stranded DNA break formation at the donor and recipient switch regions that are subsequently synapsed and ligated in a 53BP1-dependent process that remains poorly understood. The DNA damage response E3 ubiquitin ligases RNF8 and RNF168 were recently shown to facilitate recruitment of 53BP1 to sites of DNA damage. Here we show that the ubiquitination pathway mediated by RNF8 and RNF168 plays an integral part in CSR. Using the CH12F3-2 mouse B cell line that undergoes CSR to IgA at high rates, we demonstrate that knockdown of RNF8, RNF168, and 53BP1 leads to a significant decrease in CSR. We also show that 53BP1-deficient CH12F3-2 cells are protected from apoptosis mediated by the MDM2 inhibitor Nutlin-3. In contrast, deficiency in either E3 ubiquitin ligase does not protect cells from Nutlin-3-mediated apoptosis, indicating that RNF8 and RNF168 do not regulate all functions of 53BP1.53BP1 | activation-induced cytidine deaminase | DNA damage response P art of an effective immune response requires the production of antibodies of different classes, each of which mediates a different effector function. This process is initiated by activationinduced cytidine deaminase (AID), which induces class switch recombination (CSR) by deaminating deoxycytidines within Ig switch regions (1, 2). The recognition and subsequent processing of the mutated residues by base excision repair and/or mismatch repair machineries generates double-stranded DNA breaks (DSBs) at switch regions (3). In an attempt to mend the ensuing breaks, B cells mount a damage response similar to that signaled by irradiated cells (1). Ultimately, AID-induced DSBs are repaired predominantly by nonhomologous end-joining (4, 5) and to a lesser extent by an alternative end-joining pathway (6).Generally, DSBs are readily recognized by sensor-kinase protein complexes, including the Mre11-Rad50-Nbs1 (MRN)/ataxiatelangiectasia mutated (ATM), Ku70/Ku80-DNA-PKcs, and ataxiatelangiectasia and Rad3-related (ATR)-ATR-interacting protein complexes (7). Upon binding to a DSB site, these factors are activated to trigger a cascade of events that culminates in cell cycle delay and/or DNA repair (7). During this process, sequential chromatin modifications around the break sites appear to be crucial for adequate resolution of the DNA breaks. Active chromatin modification is initiated by ATM-dependent phosphorylation of the histone variant H2AX to the γH2AX form (8-10). γ-H2AX then preferentially binds the tandem-BRCA1 C-terminal domain (BRCT) motifs of mediator of DNA damage checkpoint 1 (MDC1) (11, 12), which in turn recruits more MRN/ATM, thereby amplifying the γ-H2AX signal (11, 12). Recently, it was shown that ATM also phosphorylates MDC1 at a TQxF consensus, allowing for the recruitmen...

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“…2, Path 5), as evidenced by the complete absence of switching in the Ung -/-Msh2 -/-mice. CSR is also accompanied by SHM-like mutations in the vicinity of switch regions, although deficiency in error-prone polymerases (except Pol f) [21] appears to have little effect on CSR per se [16,22]. Unlike SHM, aberrant BER and MMR in the switch region lead to double-strand breaks (DSBs) in the Sl and a partner S region (Fig.…”

Section: Somatic Hypermutation and Class Switch Recombinationmentioning

confidence: 95%

AID: a riddle wrapped in a mystery inside an enigma

et al. 2010

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To combat the ever-changing pool of pathogens we face, B cells generate highly optimized antibodies in two distinct steps. A large variety of antibodies are first generated randomly by V(D)J recombination, and then, upon encountering an antigen, antibodies are fine-tuned by somatic hypermutation and class switch recombination--both of which are initiated by the same protein, activation-induced cytidine deaminase (AID). All three processes are highly mutagenic, and mistargeting of each of these has been shown to contribute to tumorigenesis. We study these processes because they provide an excellent model to understand how highly mutagenic reactions are channeled into productive use by cells and the consequent risk this carries. In this review, we will discuss many of the outstanding questions in the field that we grapple with while developing a consistent model for AID action. We will also discuss the complexity added to these models by the recent finding that AID might be part of a demethylase complex.

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Hijacked DNA repair proteins and unchained DNA polymerases

Cited by 27 publications

References 42 publications

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination

AID: a riddle wrapped in a mystery inside an enigma

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