Immunoglobulin gene conversion: Insights from bursal B cells and the DT40 cell line

Arima, Hiroshi; Buerstedde, Jean-Marie

doi:10.1002/dvdy.10495

Cited by 105 publications

(68 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is the primary mechanism producing antibody diversity in birds (Arakawa and Buerstedde 2004) and the rabbit (Becker and Knight 1990;Sehgal et al 2000;Weinstein et al 1994;Winstead et al 1999). Birds have single functional V H and V L gene segments and many non-functional V segments upstream which act as the templates.…”

Section: Introductionmentioning

confidence: 99%

Gene conversion in human rearranged immunoglobulin genes

Darlow

Stott²

2006

Immunogenetics

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Gene conversion in human rearranged immunoglobulin genes

Darlow

Stott²

2006

Immunogenetics

View full text Add to dashboard Cite

“…One of the best cellular systems to study the mechanism of AID-induced gene conversion and hypermutation is the chicken B cell line DT40 (7). DT40 diversifies its rearranged Ig L chain gene (IgL) almost exclusively by V-templated gene conversions in an AID-dependent fashion (3).…”

mentioning

confidence: 99%

Uracil DNA Glycosylase Disruption Blocks Ig Gene Conversion and Induces Transition Mutations

Saribasak¹,

Saribasak²,

Ipek³

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Ig gene conversion is most likely initiated by activation-induced cytidine deaminase-mediated cytosine deamination. If the resulting uracils need to be further processed by uracil DNA glycosylase (UNG), UNG inactivation should block gene conversion and induce transition mutations. In this study, we report that this is indeed the phenotype in the B cell line DT40. Ig gene conversion is almost completely extinguished in the UNG-deficient mutant and large numbers of transition mutations at C/G bases accumulate within the rearranged Ig L chain gene (IgL). The mutation rate of UNG-deficient cells is about seven times higher than that of pseudo V gene-deleted (ψV−) cells in which mutations arise presumably after uracil excision. In addition, UNG-deficient cells show relatively more mutations upstream and downstream of the VJ segment. This suggests that hypermutating B cells process activation-induced cytidine deaminase-induced uracils with approximately one-seventh of uracils giving rise to mutations depending on their position.

show abstract

“…The underlying mechanism in humans is somatic hypermutation, which modifies the antigen binding region by targeted mutagenesis in the variable region of the Ig genes (1). An alternative diversification mechanism prevalent in chicken and some mammals, Ig gene conversion alters the same region by targeted homologous recombination with upstream Ig pseudogenes (2).…”

mentioning

confidence: 99%

Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Somatic hypermutation of Ig genes is initiated by transcriptioncoupled cytidine deamination in Ig loci. Error-prone processing of the resultant DNA lesions is thought to cause extensive mutagenesis, but it is presently an enigma how and why error-prone rather than error-free repair pathways are recruited. During DNA replication, recruitment of error-prone translesion polymerases may be mediated by Rad6͞Rad18-mediated ubiquitination of proliferating cell nuclear antigen, a major switchboard controlling the fidelity of DNA lesion bypass in eukaryotes. By inactivation of Rad18 in the DT40 B cell line, we show that the Rad6 pathway is involved in somatic hypermutation in these cells. Our findings imply that targeted recruitment of mutagenic polymerases by the Rad6 pathway contributes to the complex process of somatic hypermutation and provide a framework for more detailed mechanistic studies of the mutagenesis phase of secondary Ig diversification.proliferating cell nuclear antigen ͉ ubiquitination ͉ Rad6 pathway G iven the many challenges that damage cellular DNA daily, the faithful maintenance of genetic information requires the interplay of multiple DNA repair pathways. In most cases, these mechanisms ensure restoration of the original DNA sequence, preventing mutations or aberrations that may lead to impairment of cellular function. In some instances, though, a certain imprecision may be tolerated or even favored by the cell to allow for survival in critical situations. DNA repair mechanisms that are inherently imprecise are the basis of the spontaneous mutability of all genomes and may be recruited and adapted for situations where high genetic variability is mandatory for survival.The adaptive immune system of vertebrates has been shaped in coevolution with pathogenic organisms of high genetic diversity and variability. The high diversity of the primary immune repertoire established during V(D)J recombination in B and T cells generates sufficient potential for recognition of any pathogen, but the affinity of binding is often not sufficient for effective neutralization. Therefore, a second wave of diversification during acute infections ensures that the binding affinity of the antibodies produced by B lymphocytes is fine-tuned to the task at hand. The underlying mechanism in humans is somatic hypermutation, which modifies the antigen binding region by targeted mutagenesis in the variable region of the Ig genes (1). An alternative diversification mechanism prevalent in chicken and some mammals, Ig gene conversion alters the same region by targeted homologous recombination with upstream Ig pseudogenes (2).Somatic hypermutation and Ig gene conversion are related processes (3) originating from the same initial DNA lesion. The transcription-coupled deamination of cytosines by activationinduced cytidine deaminase (AID) leads to uracil that may be processed to abasic sites or strand breaks by the excision repair pathway, i.e., uracil-N-glycosylase (4, 5). The resultant DNA lesions may be repaired by mutagenesis or reco...

show abstract

Immunoglobulin gene conversion: Insights from bursal B cells and the DT40 cell line

Cited by 105 publications

References 39 publications

Gene conversion in human rearranged immunoglobulin genes

Gene conversion in human rearranged immunoglobulin genes

Uracil DNA Glycosylase Disruption Blocks Ig Gene Conversion and Induces Transition Mutations

Involvement of Rad18 in somatic hypermutation

Contact Info

Product

Resources

About