Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination

Hong Zan (), Connie Tat, Zhifang Qiu, Julia R. Taylor, Justin A. Guerrero, Tian Shen and Paolo Casali ()
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Hong Zan: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Connie Tat: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Zhifang Qiu: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Julia R. Taylor: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Justin A. Guerrero: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Tian Shen: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center
Paolo Casali: Immunology and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14244

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