Decreased Frequency of Somatic Hypermutation and Impaired Affinity Maturation but Intact Germinal Center Formation in Mice Expressing Antisense RNA to DNA Polymerase ζ

Diaz, Marilyn; Verkoczy, Laurent; Flajnik, Martin F.; Klinman, Norman R.

doi:10.4049/jimmunol.167.1.327

Cited by 142 publications

(101 citation statements)

References 65 publications

(45 reference statements)

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“…There were fewer B-cells in bone marrow and spleen, and the affinity of antibodies following immunization was reduced. In the memory B-cells of mice expressing Rev3L antisense, there were fewer somatic mutations in the Ig V H gene compared to parental controls, suggesting a decrease in overall somatic hypermutation [83]. In mice and in chicken DT40 B-cells, the dCMP transferase activity of Rev1 appears to be important for immunoglobulin diversification.…”

Section: Consequences Of Rev3l Disruption In Higher Organismsmentioning

confidence: 95%

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DNA polymerase zeta (pol ζ) in higher eukaryotes

et al. 2007

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Most current knowledge about DNA polymerase zeta (pol ζ) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol ζ can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7(MAD2B) in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

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Section: Consequences Of Rev3l Disruption In Higher Organismsmentioning

confidence: 95%

“…Mice expressing Rev3L anti-sense RNA have also been generated [83]. These mice were healthy with normal body weight and lifespan, and perhaps survived because of a low level of residual REV3L expression.…”

Section: Consequences Of Rev3l Disruption In Higher Organismsmentioning

confidence: 99%

DNA polymerase zeta (pol ζ) in higher eukaryotes

et al. 2007

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“…The DT40 system, as most other in vitro hypermutation models, does not allow substantial analyses of A͞T mutagenesis (3). Concerning G͞C-biased mutagenesis, Rad18 might function specifically during translesion synthesis over abasic sites, which is required for G͞C transversions but may also insert transitions (15,27), and͞or might be involved in the recruitment of mismatch extenders such as Pol and Pol that appear to affect the overall mutation load rather than specific subpathways (9,(32)(33)(34). Clearly, all types of mutations are negatively affected by Rad18 deficiency (Fig.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Rad18 in somatic hypermutation

Brinckmann¹,

Ertongur²,

Jungnickel³

2006

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

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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...

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“…However, it should be noted that all biochemical assays on Rev3 are performed using the yeast enzyme, as no active recombinant mammalian Rev3 has been produced so far. In transgenic mice expressing an antisense transcript against Rev3 that reduces its expression in B cells, a lower mutation frequency was observed, with no specific impact on the mutation pattern 76 . A similar observation was made in a Burkitt's lymphoma cell line (CL-01) that is induced to undergo SHM in culture, using antisense oligonucleotides against Rev3 77 .…”

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

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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Decreased Frequency of Somatic Hypermutation and Impaired Affinity Maturation but Intact Germinal Center Formation in Mice Expressing Antisense RNA to DNA Polymerase ζ

Cited by 142 publications

References 65 publications

DNA polymerase zeta (pol ζ) in higher eukaryotes

DNA polymerase zeta (pol ζ) in higher eukaryotes

Involvement of Rad18 in somatic hypermutation

DNA polymerases in adaptive immunity

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