title: Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1.
abstract: 53BP1 is a DNA damage protein that forms phosphorylated H2AX (γ-H2AX) dependent foci in a 1 Mb region surrounding DNA double-strand breaks (DSBs). In addition, 53BP1 promotes genomic stability by regulating the metabolism of DNA ends. We have compared the joining rates of paired DSBs separated by 1.2 kb to 27 Mb on chromosome 12 in the presence or absence of 53BP1. 53BP1 facilitates joining of intrachromosomal DSBs but only at distances corresponding to γ-H2AX spreading. In contrast, DNA end protection by 53BP1 is distance independent. Furthermore, analysis of 53BP1 mutants shows that chromatin association, oligomerization, and N-terminal ATM phosphorylation are all required for DNA end protection and joining as measured by immunoglobulin class switch recombination. These data elucidate the molecular events that are required for 53BP1 to maintain genomic stability and point to a model wherein 53BP1 and H2AX cooperate to repress resection of 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: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bunting
authors.forename: Isaac A
authors.initials: IA
authors.lastname: Klein
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Barlow
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Bosque
authors.forename: Elsa
authors.initials: E
authors.lastname: Callen
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D010766:Phosphorylation; D055503:Protein Multimerization; D011995:Recombination, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D000071857:Tumor Suppressor p53-Binding Protein 1; C498302:Trp53bp1 protein, mouse; C475961:gamma-H2AX protein, mouse