Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1–mutant mice

Bardwell, Philip D.; Woo, Caroline J.; Wei, Kai; Li, Ziqiang; Martín, Alberto; Sack, Stephen Z; Parris, Tchaiko; Edelmann, Winfried; Scharff, Matthew D.

doi:10.1038/ni1031

Cited by 236 publications

(200 citation statements)

References 49 publications

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“…Mice deficient in the MutL homologs Mlh1 and Pms2 have altered SHM and CSR patterns (13)(14)(15)(16)(17)(18)(19)(20). Exonuclease 1-mutant mice have altered SHM and reduced CSR (21). Interestingly, mice deficient in Mlh3 have increased SHM, suggesting that Mlh3 normally reduces the SHM mutation load (22).…”

Section: Somatic Hypermutation and Class Switch Recombination Inmentioning

confidence: 98%

Somatic Hypermutation and Class Switch Recombination in Msh6−/−Ung−/− Double-Knockout Mice

Sui¹,

Tanaka²,

Bozek³

et al. 2006

The Journal of Immunology

114

123

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Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytosine deaminase (AID). The uracil, and potentially neighboring bases, are processed by error-prone base excision repair and mismatch repair. Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR. To determine whether Msh2/Msh6 complexes which recognize single-base mismatches and loops were the only mismatch-recognition complexes required for SHM and CSR, we analyzed these processes in Msh6−/−Ung−/− mice. SHM and CSR were affected in the same degree and fashion as in Msh2−/−Ung−/− mice; mutations were mostly C,G transitions and CSR was greatly reduced, making Msh2/Msh3 contributions unlikely. Inactivating Ung alone reduced mutations from A and T, suggesting that, depending on the DNA sequence, varying proportions of A,T mutations arise by error-prone long-patch base excision repair. Further, in Msh6−/−Ung−/− mice the 5′ end and the 3′ region of Ig genes was spared from mutations as in wild-type mice, confirming that AID does not act in these regions. Finally, because in the absence of both Ung and Msh6, transition mutations from C and G likely are “footprints” of AID, the data show that the activity of AID is restricted drastically in vivo compared with AID in cell-free assays.

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Section: Somatic Hypermutation and Class Switch Recombination Inmentioning

confidence: 98%

Somatic Hypermutation and Class Switch Recombination in Msh6−/−Ung−/− Double-Knockout Mice

Sui¹,

Tanaka²,

Bozek³

et al. 2006

The Journal of Immunology

114

123

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“…4). By contrast, MSH2 deficiency results in a decreased mutagenesis at A/T bases, a phenotype that is also associated with MSH6 and Exo1 deficiency [100][101][102][103] (but which is not observed in the absence of PMS2 or MLH1, the effector partners of the mismatch repair complex) 42,104 . These contrasting phenotypes led to the proposition of two alternative phases of SHM: one mediated by UNG and generating mutations at G/C bases after uracil excision, and one mediated by MSH2-MSH6, introducing A/T mutations 98 .…”

Section: Ung Msh2 and The A/t Mutagenesis Pathwaymentioning

confidence: 98%

“…If this complex is absent, UNG will process most of the uracils and repair them error free. In wild-type cells, the MSH2-MSH6 complex recruits Exo1 103 , to excise a patch of DNA from a single-strand nick, the origin of which is yet unknown, as well as Polη, which results in mutagenic synthesis of the strand targeted by AID.…”

Section: A Model For Shm: Two Competitive Rather Than Alternative Patmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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PrefaceTo cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications of key genetic loci in each lymphoid cell. This proceeds through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the last decade to these unique DNA transactions.

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“…These translesion polymerases associate preferentially with monoubiquitylated PCNA. Mouse genetic experiments clearly demonstrated that SHM requires, in addition to MSH2 [50], MSH6 [51], EXO1 [52] and polymerase-η [53,54] also mono-ubiquitylated PCNA [55]. As SHM mutations at T/A base pairs are reduced to a similar extent in knock-in mice expressing a non-ubiquitylatable PCNA K164R variant, and in Msh2 -/-or Msh6 -/-animals [55], the origin of the mutations appears to be monoubiquitylated PCNA-mediated recruitment of error-prone DNA polymerases to MMR-generated gaps (see for [56] recent review).…”

Section: Mmr Proteins In Antibody Maturationmentioning

confidence: 99%

Mammalian mismatch repair: error-free or error-prone?

Peña-Dı́az

Jiricny

2012

Trends in Biochemical Sciences

100

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A considerable surge of interest in the mismatch repair (MMR) system has been brought about by the discovery of a link between Lynch syndrome, an inherited predisposition to cancer of the colon and other organs, and malfunction of this key DNA metabolic pathway. This review focuses on recent advances in our understanding of the molecular mechanisms of canonical MMR, which improves replication fidelity by removing misincorporated nucleotides from the nascent DNA strand. We also discuss the involvement of MMR proteins in two other processes: trinucleotide repeat expansion and antibody maturation, in which MMR proteins are required for mutagenesis rather than for its prevention. 3

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Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1–mutant mice

Cited by 236 publications

References 49 publications

Somatic Hypermutation and Class Switch Recombination in Msh6−/−Ung−/− Double-Knockout Mice

Somatic Hypermutation and Class Switch Recombination in Msh6−/−Ung−/− Double-Knockout Mice

DNA polymerases in adaptive immunity

Mammalian mismatch repair: error-free or error-prone?

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