Open AccessRad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination
Author(s) -
Hong Zan,
Connie Tat,
Zhifang Qiu,
Julia R. Taylor,
Justin A. Guerrero,
Tian Shen,
Paolo Casali
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms14244
Subject(s) - ku70 , ku80 , rad52 , non homologous end joining , dna , biology , dna repair , recombination , microbiology and biotechnology , dna repair protein xrcc4 , genetics , chemistry , gene , rad51 , dna binding protein , dna mismatch repair , transcription factor
Antibody class-switch DNA recombination (CSR) is initiated by AID-introduced DSBs in the switch (S) regions targeted for recombination, as effected by Ku70/Ku86-mediated NHEJ. Ku-deficient B cells, however, undergo (reduced) CSR through an alternative(A)-NHEJ pathway, which introduces microhomologies in S–S junctions. As microhomology-mediated end-joining requires annealing of single-strand DNA ends, we addressed the contribution of single-strand annealing factors HR Rad52 and translesion DNA polymerase θ to CSR. Compared with their Rad52 +/+ counterparts, which display normal CSR, Rad52 −/− B cells show increased CSR, fewer intra-Sμ region recombinations, no/minimal microhomologies in S–S junctions, decreased c-Myc/IgH translocations and increased Ku70/Ku86 recruitment to S-region DSB ends. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends. It also facilitates a Ku-independent DSB repair, which favours intra-S region recombination and mediates, particularly in Ku absence, inter-S–S recombination, as emphasized by the significantly greater CSR reduction in Rad52 −/− versus Rad52 +/+ B cells on Ku86 knockdown.