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

In 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 a...

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Published in:bioRxiv
Main Authors: Mahnoush Bahjat, Stratigopoulou, Maria, Pilzecker, Bas, Van Dam, Tijmen P, Mobach, Simon, Bende, Richard J, Carel Jm Van Noesel, Jacobs, Heinz E, Guikema, Jeroen E
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 31.01.2020
Cold Spring Harbor Laboratory
Edition:1.1
Subjects:
Activation-induced cytidine deaminase
Adenine
Base excision repair
Cell activation
Clonal selection
Cytidine deaminase
Cytosine
Deoxyribonucleic acid
DNA
DNA polymerase
DNA repair
DNA-directed DNA polymerase
Genomics
Germinal centers
Hypoxia
Immunology
Lesions
Lymphocytes B
Mismatch repair
Mutagenesis
Mutation
Somatic hypermutation
Thymine
Uracil
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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Summary:In 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.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
ISSN:2692-8205
2692-8205
DOI:10.1101/2020.01.30.926964