Competitive repair pathways in immunoglobulin gene hypermutation

Reynaud, Caroline; Delbos, Frédéric; Faili, Ahmad; Guéranger, Quentin; Aoufouchi, Saïd; Weill, Jean Claude

doi:10.1098/rstb.2008.0206

Cited by 27 publications

(25 citation statements)

References 41 publications

(67 reference statements)

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“…This model is in good agreement with the available data and explains very well the frequency and patterns of Ig gene hypermutation in various genetic models. Our model is in striking contrast with a model presented previously (Reynaud et al, 2009). Further studies are required to completely understand the role of cell cycle progression in the recognition and processing of AID-triggered U:G lesions.…”

Section: A Cell Cycle-based Model Of Ig Gene Hypermutationcontrasting

confidence: 73%

“…SHM is initiated by the activationinduced cytidine deaminase (AID) (Muramatsu et al, 2000), which is thought to catalyze the deamination of cytosine to uracil and generate a U:G lesion on DNA (Chaudhuri et al, 2003). generated (Di Noia and Neuberger, 2007;Maul and Gearhart, 2010;Rada et al, 1998Rada et al, , 2004Reynaud et al, 2009). Accordingly, mutations are induced during replication and repair of the AID-triggered U:G lesion by three major pathways.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Ig gene hypermutation in Ung−/−Polh−/− mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions

Li¹,

Zhao²,

Wang³

2013

Molecular Immunology

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Section: A Cell Cycle-based Model Of Ig Gene Hypermutationcontrasting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Analysis of Ig gene hypermutation in Ung−/−Polh−/− mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions

Li¹,

Zhao²,

Wang³

2013

Molecular Immunology

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“…An unknown fraction of G/C transition mutations may also result from uracils carried over replication. Models of hypermutation essentially differ on how repartition occurs between these two pathways: alternative choices, competition, and/or distribution according to the cell cycle (4,13,14).…”

mentioning

confidence: 99%

A Backup Role of DNA Polymerase κ in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase η

Faili

Stary

Delbos

et al. 2009

The Journal of Immunology

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*Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (Pol) , and display accordingly an increased skin sensitivity to UV light, as well as an altered mutation pattern of their Ig V genes in memory B cells, alteration that consists in a reduced mutagenesis at A/T bases. We previously suggested that another polymerase with a different mutation signature, Pol , is used as backup for Ig gene hypermutation in both humans and mice in cases of complete Pol deficiency, a proposition supported in this study by the analysis of Pol ؋ Pol double-deficient mice. We also describe a new XPV case, in which a splice site mutation of the first noncoding exon results in a decreased mRNA expression, a mRNA that otherwise encodes a normal Pol protein. Whereas the Pol mRNA level observed in patient's fibroblasts is one-twentieth the value of healthy controls, it is only reduced to one-fourth of the normal level in activated B cells. Memory B cells from this patient showed a 50% reduction in A/T mutations, with a spectrum that still displays a strict Pol signature. Pol thus appears as a dominant enzyme in hypermutation, its presence precluding the use of a substitute enzyme even in conditions of reduced availability. Such a dominant behavior may explain the lack of Pol signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol activity might exist. The Journal of Immunology, 2009, 182: 6353-6359. S omatic mutation at the Ig locus is initiated by the action of activation-induced cytidine deaminase (AID),4 which generates uracils from cytidine deamination in the DNA domain encoding the rearranged V gene segments (1-3). Uracils produced by DNA deamination are potent mutagens if carried over replication, giving rise to G to A or C to T transition mutations at the targeted site. However, only a fraction of the mutations observed at the H and L chain Ig loci corresponds to such a passive mutagenesis, implying that additional repair processes involving error-prone DNA synthesis, i.e., mutagenic DNA polymerases (Pol), are mobilized to spread and enlarge the mutation spectrum (4).The first experimental evidence for the implication of mutagenic polymerases in hypermutation came from the observation of Ig gene mutations in memory B cells from patients with the variant form of xeroderma pigmentosum (XPV) (5). Classical xeroderma pigmentosum diseases correspond to inactivation of one of the genes involved in nucleotide excision repair, whereas XPV corresponds to the inactivation of Pol , responsible for the error-free bypass of UV-induced thymidine dimers during replication (6, 7). Accordingly, XPV patients show an increased sensitivity to UV light with a high frequency of skin cancers. Analysis of Ig gene mutations in XPV patients showed a marked reduction, but not a suppression, of mutations at A/T bases, clearly suggesting a role for Pol in the generation of these mutations (5, 8).Studies performed in the mouse have further confirmed the major ro...

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“…Error-prone DNA polymerases during BER and MMR in GC B cells have been implicated in the spreading process that generates mutations at A/T base pairs (206, 207), raising the possibility that differential expression of these enzymes or other related factors in GC B cells could contribute to SHM spreading (208). However, since V(D)J exons are not AID targets in B cells activated in culture for CSR, this notion has not yet been tested directly.…”

Section: Perspectivementioning

confidence: 99%

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

2015

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The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination.

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Competitive repair pathways in immunoglobulin gene hypermutation

Cited by 27 publications

References 41 publications

Analysis of Ig gene hypermutation in Ung−/−Polh−/− mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions

Analysis of Ig gene hypermutation in Ung−/−Polh−/− mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions

A Backup Role of DNA Polymerase κ in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase η

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

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