DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes

10.1038/88740 ◽  
2001 ◽  
Vol 2 (6) ◽  
pp. 537-541 ◽  
Author(s):  
Xianmin Zeng ◽  
David B. Winter ◽  
Cynthia Kasmer ◽  
Kenneth H. Kraemer ◽  
Alan R. Lehmann ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Immunoglobulin Variable Genes ◽  
Variable Genes

scholarly journals 129-derived Strains of Mice Are Deficient in DNA Polymerase ι and Have Normal Immunoglobulin Hypermutation

2003 ◽  
Vol 198 (4) ◽  
pp. 635-643 ◽  
Author(s):  
John P. McDonald ◽  
Ekaterina G. Frank ◽  
Brian S. Plosky ◽  
Igor B. Rogozin ◽  
Chikahide Masutani ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Genomic Sequence ◽  
Somatic Hypermutation ◽  
Biochemical Properties ◽  
Exon 2 ◽  
Nonsense Codon ◽  
Immunoglobulin Variable Genes ◽  
Dna Polymerase Ι ◽  
Variable Genes

Recent studies suggest that DNA polymerase η (polη) and DNA polymerase ι (polι) are involved in somatic hypermutation of immunoglobulin variable genes. To test the role of polι in generating mutations in an animal model, we first characterized the biochemical properties of murine polι. Like its human counterpart, murine polι is extremely error-prone when catalyzing synthesis on a variety of DNA templates in vitro. Interestingly, when filling in a 1 base-pair gap, DNA synthesis and subsequent strand displacement was greatest in the presence of both pols ι and η. Genomic sequence analysis of Poli led to the serendipitous discovery that 129-derived strains of mice have a nonsense codon mutation in exon 2 that abrogates production of polι. Analysis of hypermutation in variable genes from 129/SvJ (Poli−/−) and C57BL/6J (Poli+/+) mice revealed that the overall frequency and spectrum of mutation were normal in polι-deficient mice. Thus, either polι does not participate in hypermutation, or its role is nonessential and can be readily assumed by another low-fidelity polymerase.

scholarly journals DNA polymerase β prevents AID-instigated mutagenic non-canonical mismatch DNA repair

2020 ◽  
Author(s):  
Mahnoush Bahjat ◽  
Maria Stratigopoulou ◽  
Bas Pilzecker ◽  
Tijmen P. van Dam ◽  
Simon Mobach ◽  
...  
Keyword(s):  
B Cells ◽  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Clonal Selection ◽  
Cytidine Deaminase ◽  
Affinity Maturation ◽  
Dna Polymerase Β ◽  
Immunoglobulin Variable Genes ◽  
Base Excision

ABSTRACTIn B cells, the error-prone repair of activation-induced cytidine deaminase (AID)-induced lesions in immunoglobulin variable genes cause somatic hypermutation (SHM) of antibody genes. Due to clonal selection in the germinal centers (GC) this active mutation process provides the molecular basis for antibody affinity maturation. AID deaminates cytosine (C) to create uracil (U) in DNA. Typically, the short patch base excision repair (spBER) effectively restores genomic U lesions. We here demonstrate that GC B cells actively degrade DNA polymerase β (Polβ), resulting in the inactivation of the gap-filling step of spBER. Consequently, lesions instigated by AID, and likely other base damages, are channeled towards mutagenic non-canonical mismatch repair (mncMMR), responsible for the vast majority of mutations at adenine and thymine (A:T) bases. Apparently, GC B cells prohibit faithful spBER, thereby favoring A:T mutagenesis during SHM. Lastly, our data suggest that the loss of Polβ relates to hypoxia that characterizes the GC microenvironment.

scholarly journals MSH2–MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes

2005 ◽  
Vol 201 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Teresa M. Wilson ◽  
Alexandra Vaisman ◽  
Stella A. Martomo ◽  
Patsa Sullivan ◽  
Li Lan ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Cytidine Deaminase ◽  
Abasic Site ◽  
Cell Extracts ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2–MSH6 mismatch repair heterodimer and DNA polymerase (pol) η, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2–MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol η in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2–MSH6 stimulates the catalytic activity of pol η in vitro. These observations suggest that the interaction between MSH2–MSH6 and DNA pol η stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.

scholarly journals DNA Polymerase η Is Involved in Hypermutation Occurring during Immunoglobulin Class Switch Recombination

2004 ◽  
Vol 199 (2) ◽  
pp. 265-270 ◽  
Author(s):  
Ahmad Faili ◽  
Said Aoufouchi ◽  
Sandra Weller ◽  
Françoise Vuillier ◽  
Anne Stary ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Sequences ◽  
Tandem Repeats ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Mutation Pattern ◽  
Immunoglobulin Locus ◽  
V Gene

Base substitutions, deletions, and duplications are observed at the immunoglobulin locus in DNA sequences involved in class switch recombination (CSR). These mutations are dependent upon activation-induced cytidine deaminase (AID) and present all the characteristics of the ones observed during V gene somatic hypermutation, implying that they could be generated by the same mutational complex. It has been proposed, based on the V gene mutation pattern of patients with the cancer-prone xeroderma pigmentosum variant (XP-V) syndrome who are deficient in DNA polymerase η (pol η), that this enzyme could be responsible for a large part of the mutations occurring on A/T bases. Here we show, by analyzing switched memory B cells from two XP-V patients, that pol η is also an A/T mutator during CSR, in both the switch region of tandem repeats as well as upstream of it, thus suggesting that the same error-prone translesional polymerases are involved, together with AID, in both processes.

Rapid cloning of any rearranged mouse immunoglobulin variable genes

1996 ◽  
Vol 43 (3) ◽  
Author(s):  
AnupamK. Dattamajumdar ◽  
DavidP. Jacobson ◽  
LeroyE. Hood ◽  
GamalE. Osman
Keyword(s):  
Mouse Immunoglobulin ◽  
Immunoglobulin Variable Genes ◽  
Variable Genes
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