Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein

Phung, Quy H.; Winter, David B.; Cranston, Aaron; Tarone, Robert E.; Bohr, Vilhelm A.; Fishel, Richard; Gearhart, Patricia J.

doi:10.1084/jem.187.11.1745

Cited by 188 publications

(179 citation statements)

References 42 publications

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“…Mismatch-repair proteins have been implicated in Ig hypermutation [49][50][51], but the potential for indirect effects, such as genomic instability and reduced proliferative potential from mismatch repair deficiency [52,53], has obscured their importance in Ig hypermutation. The fact that mismatch-repair-deficient mice display a significant alteration in the Ig mutational pattern (namely a bias for targeting of GC nucleotides) suggests a direct role in Ig hypermutation, because it is difficult to explain how a defect in proliferation would yield an alteration in the pattern of hypermutation.…”

Section: Discussionmentioning

confidence: 99%

“…Humans with mutations in the AID gene develop a type of hyper-IgM syndrome with absolute impairment in CSR and significant but not complete impairment in Ig hypermutation [47 •• ]. Given its potential function as an RNA-editing enzyme, it is very likely that AID plays a role in the modification of RNA transcripts that encode molecules critical to Ig hypermutation and CSR [46,48,49] (and perhaps Ig gene conversion?). Whether this molecule is involved in the regulation of hypermutation targeting, lesion introduction or error-prone repair remains a fascinating question that is likely to unveil novel molecules important for these mechanisms.…”

Section: Ig Hypermutation Regulation -A Possible Role For Aidmentioning

confidence: 99%

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Somatic immunoglobulin hypermutation

Diaz

Casali

2002

Current Opinion in Immunology

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Immunoglobulin hypermutation provides the structural correlate for the affinity maturation of the antibody response. Characteristic modalities of this mechanism include a preponderance of pointmutations with prevalence of transitions over transversions, and the mutational hotspot RGYW sequence. Recent evidence suggests a mechanism whereby DNA-breaks induce error-prone DNA synthesis in immunoglobulin V(D)J regions by error-prone DNA polymerases. The nature of the targeting mechanism and the trans-factors effecting such breaks and their repair remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Section: Ig Hypermutation Regulation -A Possible Role For Aidmentioning

confidence: 99%

Somatic immunoglobulin hypermutation

Diaz

Casali

2002

Current Opinion in Immunology

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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: 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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“…Genes that encode proteins involved in postmismatch recognition functions of MMR have also been shown to be involved in SHM and CSR. 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).…”

Section: Somatic Hypermutation and Class Switch Recombination Inmentioning

confidence: 99%

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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Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein

Cited by 188 publications

References 42 publications

Somatic immunoglobulin hypermutation

Somatic immunoglobulin hypermutation

DNA polymerases in adaptive immunity

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

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