Molecular Mechanisms of Antibody Somatic Hypermutation

Noia, Javier M. Di; Neuberger, Michael S.

doi:10.1146/annurev.biochem.76.061705.090740

Cited by 921 publications

(1,012 citation statements)

References 139 publications

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“…Inactivation of MSH2, MSH6, PMS2, MLH1, or EXO1 reduces the recovery of somatic mutations that occur specifically at A-T base pairs at immunoglobulin loci. A two-stage model has been invoked in which deamination of cytosines at G-C base pairs by activation-induced cystidine deaminse (AID) leads to G-U mispairs (reviewed in Di Noia and Neuberger, 2007). These are targets for base excision repair (BER).…”

Section: Other Functions Of Mmrmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

387

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Section: Other Functions Of Mmrmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

387

359

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“…The discovery of activation-induced cytidine deaminase (AID) provided a clue to this problem [38][39][40] . It is now generally accepted that the deamination of cytidines into uracils by AID is the initiating event that allows the specific recruitment of factors involved in SHM, CSR or gene conversion 41 . Uracils can normally be excised by several uracil glycosylases and replaced by the base-excision repair pathway, which faithfully restores the original DNA sequence.…”

Section: Somatic Hypermutation and Dna Polymerasesmentioning

confidence: 99%

“…These abasic sites are bypassed by several translesion polymerases, such as Rev1 and others that remain to be identified. Rather than splitting hypermutation in phase I and phase II according to Neuberger and colleagues 41 , this model proposes an A/T vs. G/C mutation model that is essentially cell-cycle and/or DNA structure dependent. …”

Section: Acknowledgementsmentioning

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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“…AID deaminates cytidine (dC) to uracil (dU) within the Ig variable (IgV) regions, triggering somatic hypermutation and, in some species including birds, gene conversion, a process by which the rearranged V gene recombines with upstream pseudogenes (Di Noia & Neuberger, 2007). …”

Section: Introductionmentioning

confidence: 99%

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

et al. 2016

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Immunoglobulin diversification is driven by activation‐induced deaminase (AID), which converts cytidine to uracil within the Ig variable (IgV) regions. Central to the recruitment of AID to the IgV genes are factors that regulate the generation of single‐stranded DNA (ssDNA), the enzymatic substrate of AID. Here, we report that chicken DT40 cells lacking variant histone H3.3 exhibit reduced IgV sequence diversification. We show that this results from impairment of the ability of AID to access the IgV genes due to reduced formation of ssDNA during IgV transcription. Loss of H3.3 also diminishes IgV R‐loop formation. However, reducing IgV R‐loops by RNase HI overexpression in wild‐type cells does not affect IgV diversification, showing that these structures are not necessary intermediates for AID access. Importantly, the reduction in the formation of AID‐accessible ssDNA in cells lacking H3.3 is independent of any effect on the level of transcription or the kinetics of RNAPII elongation, suggesting the presence of H3.3 in the nucleosomes of the IgV genes increases the chances of the IgV DNA becoming single‐stranded, thereby creating an effective AID substrate.

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Molecular Mechanisms of Antibody Somatic Hypermutation

Cited by 921 publications

References 139 publications

DNA mismatch repair: Molecular mechanism, cancer, and ageing

DNA mismatch repair: Molecular mechanism, cancer, and ageing

DNA polymerases in adaptive immunity

Histone H3.3 promotes IgV gene diversification by enhancing formation of AID ‐accessible single‐stranded DNA

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