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Phf5a regulates DNA repair in class switch recombination via p400 and histone H2A variant deposition
Author(s) -
Begum Nasim A,
Haque Farazul,
Stanlie Andre,
Husain Afzal,
Mondal Samiran,
Nakata Mikiyo,
Taniguchi Takako,
Taniguchi Hisaaki,
Honjo Tasuku
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106393
Subject(s) - library science , histone , medicine , political science , biology , dna , genetics , computer science
Antibody class switch recombination (CSR) is a locus‐specific genomic rearrangement mediated by switch (S) region transcription, activation‐induced cytidine deaminase (AID)‐induced DNA breaks, and their resolution by non‐homologous end joining (NHEJ)‐mediated DNA repair. Due to the complex nature of the recombination process, numerous cofactors are intimately involved, making it important to identify rate‐limiting factors that impact on DNA breaking and/or repair. Using an siRNA‐based loss‐of‐function screen of genes predicted to encode PHD zinc‐finger‐motif proteins, we identify the splicing factor Phf5a/Sf3b14b as a novel modulator of the DNA repair step of CSR. Loss of Phf5a severely impairs AID‐induced recombination, but does not perturb DNA breaks and somatic hypermutation. Phf5a regulates NHEJ‐dependent DNA repair by preserving chromatin integrity to elicit optimal DNA damage response and subsequent recruitment of NHEJ factors at the S region. Phf5a stabilizes the p400 histone chaperone complex at the locus, which in turn promotes deposition of H2A variant such as H2AX and H2A.Z that are critical for the early DNA damage response and NHEJ, respectively. Depletion of Phf5a or p400 blocks the repair of both AID‐ and I‐SceI ‐induced DNA double‐strand breaks, supporting an important contribution of this axis to programmed as well as aberrant recombination.