DNA Polymerase η Is Involved in Hypermutation Occurring during Immunoglobulin Class Switch Recombination

Faili, Ahmad; Aoufouchi, Saïd; Weller, Sandra; Vuillier, Françoise; Stary, Anne; Sarasin, Alain; Reynaud, Claude‐Agnès; Weill, Jean‐Claude

doi:10.1084/jem.20031831

Cited by 119 publications

(109 citation statements)

References 28 publications

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“…A reduced mutation frequency at A/T bases was observed in these patients 54,55 , an observation that was further confirmed in Polη-deficient mice [56][57][58] (Fig.4).…”

Section: Polη the Study Of Patients Affected By The Xeroderma Pigmensupporting

confidence: 68%

“…Polη-dependent mutations have been observed upstream of switch junctions in human and mouse B cells, but there does not seem to be any quantitative alteration in CSR in the absence of this enzyme [55][56][57]108 . As DNA sequences surrounding switch junctions have no function once CSR has occurred, these mutations are likely to have no physiological role.…”

Section: Csr Gene Conversion and Dna Polymerasesmentioning

confidence: 97%

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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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“…A reduced mutation frequency at A/T bases was observed in these patients 54,55 , an observation that was further confirmed in Polη-deficient mice [56][57][58] (Fig.4).…”

Section: Polη the Study Of Patients Affected By The Xeroderma Pigmensupporting

confidence: 68%

Section: Csr Gene Conversion and Dna Polymerasesmentioning

confidence: 97%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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“…However, it has since been shown that Artemis is indeed involved in CSR, where its nuclease activity may function in resolving more complex lesions that are generated during CSR 26. The polymerases involved in CSR are thought to include the error prone polymerases, polymerase η and REV1 27, 28…”

Section: Mechanisms Of Recombination In Lymphoid Cellsmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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“…A:T mutations are reduced by Ͼ80% in POLH-deficient mice (13)(14)(15)(16)18). We recently found that these mice produced decreased serum titers of high-affinity Abs against a T-dependent Ag and that this was associated with a reduced frequency and altered patterns of amino acid substitutions in the complementary determining region of the Ig V H genes in the responding B cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic and biochemical evidence suggests that components of the mismatch repair (MMR) system, including MutS homolog (MSH) 2, MSH6, exonuclease (EXO) 1, and proliferating cell nuclear Ag (PCNA), as well as DNA polymerase (POLH), are required for the induction of A:T mutations (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). It has been proposed that the AID-triggered U:G lesion is recognized by the MSH2/6 heterodimer, followed by EXO-1-mediated strand degradation that generates a gap in the damaged DNA strand.…”

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confidence: 99%

Induction of A:T Mutations Is Dependent on Cellular Environment but Independent of Mutation Frequency and Target Gene Location

Ukai

Ishimaru

Ouchida

et al. 2008

The Journal of Immunology

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Based on its substrate specificity, activation-induced cytidine deaminase can directly induce C:G mutations in Ig genes. However the origin of A:T mutations, which occur in a similar proportion in germinal center (GC) B cells, is unclear. Genetic evidence suggests that the induction of A:T mutations requires the components of the mismatch repair system and DNA polymerase (POLH). We found that fibroblasts and GC B cells expressed similar levels of the mismatch repair components, but nonetheless the fibroblasts failed to generate a significant proportion of A:T mutations in a GFP reporter gene even after POLH overexpression. To investigate whether the ability to generate A:T mutations is dependent on the cellular environment (i.e., GC B cell or fibroblast) or the target gene (i.e., Ig or GFP), we developed a mutation detection system in a human GC-like cell line. We introduced a GFP gene with a premature stop codon into Ramos cells and compared the activation-induced cytidine deaminaseinduced mutations in the endogenous V H and the transgenic GFP genes. Remarkably, a high proportion of A:T mutations was induced in both genes. Ectopic expression of POLH did not further increase the proportion of A:T mutations but diminished the strand bias of these mutations that is normally observed in V H genes. Intriguingly, the total mutation frequency in the GFP gene was consistently one-fifth of that in the V H gene. These results demonstrate that the ability to generate A:T mutations is dependent on the GC B cell environment but independent of the mutation frequency and target gene location.

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DNA Polymerase η Is Involved in Hypermutation Occurring during Immunoglobulin Class Switch Recombination

Cited by 119 publications

References 28 publications

DNA polymerases in adaptive immunity

DNA polymerases in adaptive immunity

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Induction of A:T Mutations Is Dependent on Cellular Environment but Independent of Mutation Frequency and Target Gene Location

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