期刊
GENES & DEVELOPMENT
卷 36, 期 7-8, 页码 433-450出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.349438.122
关键词
somatic hypermutation; HMCES; AID; base excision repair; mismatch repair; antibody affinity maturation
资金
- Gruber Science Fellowship
- National Science Foundation Graduate Research Fellowship
- Leukemia and Lymphoma Society grant [5463-18]
- National Institutes of Health [R01 AI127642, K99/R00 CA248835, R35 CA210043]
The DNA repair factor HMCES can strongly suppress deletions, facilitating the production of antigen-specific antibodies. Their findings propose a novel model for protecting Ig gene integrity during SHM.
Here, Wu et al. demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of somatic hypermutation in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. Their findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes. Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair (MMR) pathways. Such uracil processing creates DNA strand breaks and is susceptible to the generation of deleterious deletions. Here, we demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of SHM in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. The deletion-prone repair pathway suppressed by HMCES operates downstream from the uracil glycosylase UNG and is mediated by the combined action of BER factor APE2 and MMR factors MSH2, MSH6, and EXO1. HMCES's ability to shield against deletions during SHM requires its capacity to form covalent cross-links with abasic sites, in sharp contrast to its DNA end-joining role in class switch recombination but analogous to its genome-stabilizing role during DNA replication. Our findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes.
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