Somatic Hypermutation in Muts Homologue (Msh)3-, Msh6-, and Msh3/Msh6-Deficient Mice Reveals a Role for the Msh2–Msh6 Heterodimer in Modulating the Base Substitution Pattern

Wiesendanger, Margrit; Kneitz, Burkhard; Edelmann, Winfried; Scharff, Matthew D.

doi:10.1084/jem.191.3.579

Cited by 186 publications

(142 citation statements)

References 32 publications

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“…1, pie charts). The unchanged mutation frequencies in Ung Ϫ/Ϫ mice and the reduced mutations in the secondary response of Msh6 Ϫ/Ϫ mice agrees with previous findings in Ung Ϫ/Ϫ mice (5, 26), Msh6 Ϫ/Ϫ mice (7,9), and Msh2 Ϫ/Ϫ mice (10), respectively. Thus, production of Msh6, as well as Msh2, which together are involved in mismatch repair of single base mismatches or loops, appears to increase the mutation frequency.…”

Section: Resultssupporting

confidence: 91%

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

Sui¹,

Tanaka²,

Bozek³

et al. 2006

The Journal of Immunology

116

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: Resultssupporting

confidence: 91%

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

Sui¹,

Tanaka²,

Bozek³

et al. 2006

The Journal of Immunology

116

123

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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%

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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“…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%

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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Somatic Hypermutation in Muts Homologue (Msh)3-, Msh6-, and Msh3/Msh6-Deficient Mice Reveals a Role for the Msh2–Msh6 Heterodimer in Modulating the Base Substitution Pattern

Cited by 186 publications

References 32 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

Somatic immunoglobulin hypermutation

DNA polymerases in adaptive immunity

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