Cutting Edge: Hypermutation in Ig V Genes from Mice Deficient in the MLH1 Mismatch Repair Protein

Phung, Quy H.; Winter, David B.; Alrefai, Rudaina; Gearhart, Patricia J.

doi:10.4049/jimmunol.162.6.3121

Cited by 53 publications

(1 citation statement)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rev1 and other error-prone DNA polymerases are believed to bypass AP sites creating C to G or C to A transversion mutations at the C/G sites of AID targets [40][41][42] . Further processing of U:G mismatches by non-canonical mismatch repair factors [43][44][45][46][47][48][49] . engaged with PCNA K164 monoubiquitination [50][51][52] and DNA polymerase eta [53][54][55][56][57] permits error-prone repair at A/T sites flanking uracil.…”

Section: Discussionmentioning

confidence: 99%

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Mu,

Chen,

Plummer

et al. 2024

Preprint

View full text Add to dashboard Cite

Mammalian Uracil DNA glycosylase (UNG) removes uracils and initiates high-fidelity base excision repair to maintain genomic stability. During B cell development, activation-induced cytidine deaminase (AID) creates uracils that UNG processes in an error-prone fashion to accomplish immunoglobulin (Ig) somatic hypermutation (SHM) or class switch recombination (CSR). The mechanism that governs high-fidelity versus mutagenic uracil repair is not understood. The B cell tropic gammaherpesvirus (GHV) encodes a functional homolog of UNG that can process AID induced genomic uracils. GHVUNG does not support hypermutation, suggesting intrinsic properties of UNG influence repair outcome. Noting the structural divergence between the UNGs, we define the RPA interacting motif as the determinant of mutation outcome. UNG or RPA mutants unable to interact with each other, only support high-fidelity repair. In B cells, transversions at the Ig variable region are abated while CSR is supported. Thus UNG-RPA governs the generation of mutations and has implications for locus specific mutagenesis in B cells and deamination associated mutational signatures in cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Mu,

Chen,

Plummer

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Immunoglobulin V? light chain gene analysis in patients with Sj�gren's syndrome

Heimbächer¹,

Hansen²,

Jacobi³

et al. 2001

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective Patients with Sjögren's syndrome (SS) have characteristic lymphocytic infiltration of the salivary glands with a previously reported predominance of Vκ‐bearing B cells and produce a variety of autoantibodies, indicating that there is a humoral autoimmune component in this syndrome. This study was undertaken to determine whether there are primary deviations of immunoglobulin V gene usage, differences in somatic hypermutation, defects of selection, or indications for perturbances of B cell maturation in SS. Methods Individual peripheral B cells from patients with SS were analyzed for their Ig V gene usage, and the findings were compared with results in normal controls. Results Molecular differences, as reflected by findings in the nonproductive Vκ repertoire of the patients, were identified by an enhanced usage of Jκ2 gene segments and a lack of mutational targeting toward RGYW/WRCY sequences compared with controls. A greater usage of Vκ1 family members and a reduced frequency of Vκ3 gene segments in the productive repertoire suggested differences in selection, possibly driven by antigen. Overall positive selection for mutations, especially for replacements in the complementarity‐determining region and for mutations in RGYW/WRCY, similar to that found in controls, was detected. Conclusion Disturbances of strictly regulated B cell maturation, during early B cell development as indicated by prominent Jκ2 gene usage and during germinal center reactions as indicated by a lack of targeting of the hypermutation mechanism, might contribute to the emergence of autoimmunity in SS.

show abstract

Somatic hypermutation and mismatch repair in non-B cells

et al. 2005

View full text Add to dashboard Cite

Mismatch repair contributes to hypermutation in B lymphocytes, both by increasing the frequency of mutations and by changing the mutational patterns. In this paper, we investigated whether or not mismatch repair influences activation-induced cytidine deaminase (AID)-mediated hypermutation in a non-B lymphocyte line. We did so by regulating expression of MutL homologue MLH 1, which is essential in mismatch repair, in a kidney cell line that had been transduced by an AID-containing vector. Whether or not MLH1 was expressed, we found no difference in the mutation rates of an indicator gene. We conclude that in order to contribute to hypermutation, mismatch repair needs additional factors that are present in activated B lymphocytes, but absent in the cell line investigated. IntroductionSomatic hypermutation contributes to antibody diversity through introduction of point mutations into the variable (V) region of immunoglobulin sequences [1]. The mutation rate in mice and humans is about 10 6 -fold higher than the spontaneous mutation rate in most other genes [2]. Targeting of somatic hypermutation to the Ig loci remains a subject of debate, since genomic sites other than the Ig loci have been reported to support hypermutation to various degrees [3][4][5][6]. However, somatic hypermutation is triggered by and restricted to the expression of the activation-induced cytidine deaminase (AID) enzyme in activated germinal center B cells [7][8][9][10]. Ectopic expression of AID in hybridomas [11], non-B cells [12,13] and even E. coli [14] results in a mutator phenotype. In conjunction with replication protein A (RPA) [15], AID acts on single-stranded DNA during transcription and deaminates dC into dU [16][17][18]. If the mismatch is not repaired, it results in a C?T transition, which is the predominant mutation during ectopic AID expression in cell lines and E. coli. After introduction of the G-U mismatch, various pathways fix the mutation in the genome (reviewed in [19]). For example, the uracil N-glycosylase (UNG) removes the uracil generated by AID [20]. If the resulting abasic site is converted by an AP-endonuclease into a singlestrand nick and subsequently repaired via the base excision pathway, no mutation is generated. But if the abasic site is not removed, any base can be introduced during replication [21]. Alternatively, although debated [22], mismatch repair (MMR) may sense G-U mispairing and set off a sequence of events that introduces further mutations rather than restore the original base pair sequence [23] (reviewed in [24] [39]. Cancer predisposition is linked to germ-line mutations in MMR genes; most mutations associated with HNPCC were found in hMLH1, hMSH2, and hMSH6 genes [40], while mutations in hPMS2 were reported sporadically. The majority of all HNPCC-causing mutations were found in hMLH1, focusing the interest on the analysis of pathogenic hMLH1 variants [41]. Although loss of EXO1, FEN1 and PCNA function also results in a mutator phenotype, it does not seem to significantly contribute to HNPCC forma...

show abstract

Cutting Edge: Hypermutation in Ig V Genes from Mice Deficient in the MLH1 Mismatch Repair Protein

Cited by 53 publications

References 29 publications

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Immunoglobulin V? light chain gene analysis in patients with Sj�gren's syndrome

Somatic hypermutation and mismatch repair in non-B cells

Contact Info

Product

Resources

About