Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions

Maul, Robert W.; Saribasak, Huseyin; Martomo, Stella A.; McClure, Rhonda L.; Yang, William W.; Vaisman, Alexandra; Gramlich, H.; Schatz, David G.; Woodgate, Roger; Wilson, David M.; Gearhart, Patricia J.

doi:10.1038/ni.1970

Cited by 117 publications

(106 citation statements)

References 55 publications

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“…Other biochemical studies that substantiate AID's role as a DNA deamination enzyme include the observations that AID is found to be associated with transcriptionally active switch sequences in CSR-stimulated primary B cells via chromatin immunoprecipitation (ChIP) assays ) and a recent study that revealed the presence of deoxyuracil residues at regions of AID-generated mutations, thereby contributing to the already impressive volume of evidence that points toward AID as a DNA cytidine deaminase in B cells (Maul et al 2011). …”

Section: Discovery Of Aid As 'B-cell Mutator Factor'mentioning

confidence: 99%

Regulation of AID, the B-cell genome mutator

et al. 2013

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The mechanisms by which B cells somatically engineer their genomes to generate the vast diversity of antibodies required to challenge the nearly infinite number of antigens that immune systems encounter are of tremendous clinical and academic interest. The DNA cytidine deaminase activation-induced deaminase (AID) catalyzes two of these mechanisms: class switch recombination (CSR) and somatic hypermutation (SHM). Recent discoveries indicate a significant promiscuous targeting of this B-cell mutator enzyme genome-wide. Here we discuss the various regulatory elements that control AID activity and prevent AID from inducing genomic instability and thereby initiating oncogenesis.

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Section: Discovery Of Aid As 'B-cell Mutator Factor'mentioning

confidence: 99%

Regulation of AID, the B-cell genome mutator

et al. 2013

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“…Second, modified bases within the DNA context are targeted principally by base excision repair [17] and, in some cases, by the mismatch repair machinery [18], or, rarely, by nucleotide excision repair [19] as well. Recently, it has became evident that the cellular 'infrastructure' for base excision and mismatch repair is also exploited in signal transduction leading to immunoglobulin gene diversification and active DNA demethylation [20][21][22][23][24]. Hence, the distinction between the harmful versus signalling role of modified bases becomes less clear and such definitions require an assessment of the cellular context (cell status, developmental stage, cell cycle stage, etc.)…”

Section: Non-orthodox Bases In Dna: Production and Eliminationmentioning

confidence: 99%

Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

2014

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The occurrence of modified bases in DNA is attributed to some major factors: incorporation of altered nucleotide building blocks and chemical reactions or radiation effects on bases within the DNA structure. Several enzyme families are involved in preventing the incorporation of noncanonical bases playing a 'sanitizing' role. The catalytic mechanism of action of these enzymes has been revealed for a number of representatives in clear structural and kinetic detail. In this review, we focus in detail on those examples where clear evidence has been produced using high-resolution structural studies. Comparing the protein fold and architecture of the enzyme active sites, two main classes of sanitizing deoxyribonucleoside triphosphate pyrophosphatases can be assigned that are distinguished by the site of nucleophilic attack. In enzymes associated with attack at the a-phosphorus, it is shown that coordination of the c-phosphate group is also ensured by multiple interactions. By contrast, enzymes catalyzing attack at the b-phosphorus atom mainly coordinate the a-and the b-phosphate only. Characteristic differences are also observed with respect to the role of the metal ion cofactor (Mg 2+ ) and the coordination of nucleophilic water. Using different catalytic mechanisms embedded in different protein folds, these enzymes present a clear example of convergent evolution.

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“…Powerful genetic evidence for the role of the base excision repair (BER) machinery in the processing of AID-induced DNA lesions stems from the identification of mutations in the gene encoding uracil DNA glycosylase, UNG, from a subset of hyper-IgM syndrome patients (Imai et al, 2003). Furthermore, genetic ablation of UNG in mice leads to the detection of uracil in the DNA of immunoglobulin genes, a significant increase in transition mutations at dC/dG pairs without affecting dA/dT pairs, and reduced SHM and CSR (Maul et al, 2011;Rada et al, 2002). These data suggest that uracil excision at Igh-V and switch regions is inhibited by UNG deficiency and that replication over increased dU/dG lesions leads to dT/dA mutations (Figure 3).…”

Section: Molecular Cellmentioning

confidence: 99%

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

Nussenzweig¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE: March 20142. REPORT TYPE Annual 3. DATES COVERED (From -To) PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERNational Cancer Institute Bethesda, MD 20892 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical ResearchAnd Materiel Command Fort Detrick, MD 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT :Approved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACTOur proposal is to explore the novel notion that it may be possible to restore near normal HR activity in Brca1 cells and tissues. We believe that this phenomenon will lead to targeted therapies to reduce lifetime risk of tumor formation in BRCA1 and potentially BRCA2 carriers. SUBJECT TERMSBRCA1, 53BP1, cancer biology, DNA repair, tumorigenesis. Appendices……………………………………………………………………………..9 IntroductionGenomic instability is a hallmark of cancer. Central to a cells ability to maintain genomic stability are systems that monitor and repair DNA double strand breaks (DSBs). The objective of this study is to understand how the choice of pathways used to repair DNA damage determines whether the repair is error free or causes genomic instability. In mammalian cells, homologous recombination (HR) and nonhomologous end joining (NHEJ) are the two major pathways involved in the repair of DNA DSBs. The Brca1 gene is required for DNA repair by homologous recombination and normal embryonic development. The protein 53BP1 promotes ligation and facilitates end joining. In previous studies, we have demonstrated that Brca1 and 53BP1 can compete for the processing of DSBs and that 53BP1 can promote genomic instability in the absence of Brca1. Thus, the tumor suppressive function of Brca1 does not appear to be absolute and can be modulated by altering the ability of cells to carryout NHEJ. Our study focuses on shifting the balance between these two repair pathways (HR and NHEJ) to restore error free repair and genomic stability. We believe that a better understanding of mechanisms of DSB repair pathway choice may have ...

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Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions

Cited by 117 publications

References 55 publications

Regulation of AID, the B-cell genome mutator

Regulation of AID, the B-cell genome mutator

Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

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