53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination.
Class switch recombination (CSR) diversifies antibodies by joining highly repetitive DNA elements, which are separated by 60-200 kbp. CSR is initiated by activation-induced cytidine deaminase, an enzyme that produces multiple DNA double-strand breaks (DSBs) in switch regions. Switch regions are joined by a mechanism that requires an intact DNA damage response and classical or alternative nonhomologous end joining (A-NHEJ). Among the DNA damage response factors, 53BP1 has the most profound effect on CSR. We explore the role of 53BP1 in intrachromosomal DNA repair using I-SceI to introduce paired DSBs in the IgH locus. We find that the absence of 53BP1 results in an ataxia telangiectasia mutated-dependent increase in DNA end resection and that resected DNA is preferentially repaired by microhomology-mediated A-NHEJ. We propose that 53BP1 favors long-range CSR in part by protecting DNA ends against resection, which prevents A-NHEJ-dependent short-range rejoining of intra-switch region DSBs.
Bothmer
Anne
A
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Robbiani
Davide F
DF
Feldhahn
Niklas
N
Gazumyan
Anna
A
Nussenzweig
Andre
A
Nussenzweig
Michel C
MC
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone; D023902:Chromosome Pairing / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D019426:Integrases / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011995:Recombination, Genetic / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C498302:Trp53bp1 protein, mouse; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D015847:Interleukin-4; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases; D015252:Deoxyribonucleases, Type II Site-Specific; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase