Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination

Imai, Kohsuke; Slupphaug, Geir; Lee, Wen I.; Revy, Patrick; Nonoyama, Shigeaki; Catalan, Nadia; Yel, Leman; Forveille, Monique; Kavli, Bodil; Krokan, Hans E.; Ochs, Hans D.; Fischer, Alain; Durandy, Anne

doi:10.1038/ni974

Cited by 568 publications

(429 citation statements)

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“…It is known, for example, that deletion of genes for two of the BER enzymes in mouse models inactivates the SHM process: AID-deficient mice and UDG-deficient mice have a complete loss of, and altered SHM, respectively [11,30,31]. In human B cells, down-regulation of DNA pol ι eliminated induced SHM [32,33], and in a mouse model, mutation of the pol Q gene resulted in lower induced mutagenesis in the V-region [9,34].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

et al. 2007

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Somatic hypermutation (SHM) is a fundamental process in immunoglobulin gene maturation that results in increased affinity of antibodies toward antigens. In one hypothesis explaining SHM in human B cells, the process is initiated by enzymatic deamination of cytosine to uracil in the immunoglobulin gene V-region and this in turn triggers mutation-prone forms of uracil-DNA base excision repair (BER). Yet, an uncertainty with this model is that BER of uracil-DNA in mammalian cells is generally error-free, wherein DNA polymerase β (pol β) conducts gap-filling synthesis by insertion of bases according to Watson-Crick rules. To evaluate this inconsistency, we examined pol β expression in various SHM proficient human BL2 cell line subclones. We report that expression of pol β in SHM proficient cell lines was strongly down-regulated. In contrast, in other BL2 subclones, we found that SHM was deficient and that pol β expression was much higher than in the SHM proficient subclones. We also found that overexpression of recombinant human pol β in a SHM proficient subclone abrogated its capacity for SHM. These results suggest that down-regulation of the normal BER gap-filling DNA polymerase, pol β, accompanies induced SHM in BL2 cells. This is consistent with the hypothesis that normal error-free BER must be silenced to make way for an error-prone BER process that may be required during somatic hypermutation.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

et al. 2007

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“…In addition to DNA repair, UNG2 is also involved in the somatic hypermutation and class switch recombination that yield secretory, high-affinity antibodies in B lymphocytes. Mutations in both alleles of UNG result in a hyper-immunoglobulin M (IgM) syndrome with life-threatening infections (25). Furthermore, UDG has recently been demonstrated to be essential for translocation between c-myc and the IgH locus (Igh), which is a characteristic feature of Burkitt's lymphoma (57).…”

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confidence: 99%

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

Huang

Wang

et al. 2007

J Virol

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Uracil-DNA glycosylases (UDGs) of the uracil-N-glycosylase (UNG) family are the primary DNA repair enzymes responsible for removal of inappropriate uracil from DNA. Recent studies further suggest that the nuclear human UNG2 and the UDGs of large DNA viruses may coordinate with their DNA polymerase accessory factors to enhance DNA replication. Based on its amino acid sequence, the putative UDG of Epstein-Barr virus (EBV), BKRF3, belongs to the UNG family of proteins, and it was demonstrated previously to enhance oriLyt-dependent DNA replication in a cotransfection replication assay. However, the expression and enzyme activity of EBV BKRF3 have not yet been characterized. In this study, His-BKRF3 was expressed in bacteria and purified for biochemical analysis. Similar to the case for the Escherichia coli and human UNG enzymes, His-BKRF3 excised uracil from single-stranded DNA more efficiently than from double-stranded DNA and was inhibited by the purified bacteriophage PBS1 inhibitor Ugi. In addition, BKRF3 was able to complement an E. coli ung mutant in rifampin and nalidixic acid resistance mutator assays. The expression kinetics and subcellular localization of BKRF3 products were detected in EBV-positive lymphoid and epithelial cells by using BKRF3-specific mouse antibodies. Expression of BKRF3 is regulated mainly by the immediateearly transcription activator Rta. The efficiency of EBV lytic DNA replication was slightly affected by BKRF3 small interfering RNA (siRNA), whereas cellular UNG2 siRNA or inhibition of cellular and viral UNG activities by expressing Ugi repressed EBV lytic DNA replication. Taking these results together, we demonstrate the UNG activity of BKRF3 in vitro and in vivo and suggest that UNGs may participate in DNA replication or repair and thereby promote efficient production of viral DNA.

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“…This was indeed exemplified by analyzing UNG-deficient mice [45]. Likewise, an autosomal form of HIGM in humans was ascribed to an UNG deficiency [46]. Although CSR is profoundly affected in these patients, the frequency of SHM is normal but the pattern of the mutations is biased towards transitions at G/C residues, a characteristic shared by UNG-deficient mice.…”

Section: Ung Deficiency and Morementioning

confidence: 94%

“…The enzyme uracil-N-glycolsylase (UNG), a key constituent of the base excision repair (BER) pathway, recognizes U/G mismatches and excises the uracil from DNA, thus creating an abasic site. As discussed below, the role of UNG in CSR has been substantiated by analyzing UNG-deficient conditions in both human and mice [45,46]. An enonuclease then further processes this DNA modification by creating an ssDNA nick.…”

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DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination

Cited by 568 publications

References 44 publications

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

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