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

Nat Commun. 2017 Feb 8;8:14244. doi: 10.1038/ncomms14244.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • Cytidine Deaminase / metabolism
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair / genetics
  • DNA End-Joining Repair / immunology*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / immunology
  • DNA-Directed DNA Polymerase / metabolism
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin Switch Region / genetics
  • Ku Autoantigen / genetics
  • Ku Autoantigen / immunology
  • Ku Autoantigen / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Small Interfering / metabolism
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / immunology
  • Rad52 DNA Repair and Recombination Protein / metabolism*
  • Recombinational DNA Repair / immunology*
  • Sulfonamides


  • RAD52 protein, human
  • RNA, Small Interfering
  • Rad52 DNA Repair and Recombination Protein
  • Rad52 protein, mouse
  • Sulfonamides
  • 1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione
  • DNA polymerase theta
  • DNA-Directed DNA Polymerase
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
  • XRCC5 protein, human
  • Xrcc5 protein, mouse
  • Xrcc6 protein, human
  • Xrcc6 protein, mouse
  • Ku Autoantigen