title: 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Bothmer
authors.forename: Davide F
authors.initials: DF
authors.lastname: Robbiani
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: 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)
chemical_list: 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