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PMID: 21549309 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1.

Molecular cell ·Vol. 42 ·No. 3 ·2011-05-06 ·Pages 319-29

Bothmer A, Robbiani DF, Di Virgilio M, Bunting SF, Klein IA, Feldhahn N, Barlow J, Chen HT, Bosque D, Callen E, Nussenzweig A, Nussenzweig MC

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.

MeSH Terms
Animals B-Lymphocytes/metabolism Binding Sites Blotting, Western Cells, Cultured Chromatin/metabolism Chromosomal Proteins, Non-Histone/chemistry,genetics,metabolism DNA Breaks, Double-Stranded DNA Repair DNA-Binding Proteins/chemistry,genetics,metabolism Flow Cytometry Histones/metabolism Immunoglobulin Class Switching/genetics Mice Mice, Inbred C57BL Mice, Knockout Models, Genetic Phosphorylation Protein Multimerization Recombination, Genetic Tumor Suppressor p53-Binding Protein 1
Chemicals
Chromatin Chromosomal Proteins, Non-Histone DNA-Binding Proteins H2AX protein, mouse Histones Trp53bp1 protein, mouse Tumor Suppressor p53-Binding Protein 1
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Bothmer Anne
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Robbiani Davide F
Di Virgilio Michela
Bunting Samuel F
Klein Isaac A
Feldhahn Niklas
Barlow Jacqueline
Chen Hua-Tang
Bosque David
Callen Elsa
Nussenzweig André
Nussenzweig Michel C
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.03.019
Published
2011-05-06
Pages
319-29
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3142663
Subset
IM
Grants
NIAID NIH HHS · R01 AI037526 · United States
NIGMS NIH HHS · GM07739 · United States
Howard Hughes Medical Institute · United States
NIAID NIH HHS · R01 AI072529 · United States
Intramural NIH HHS · United States
NIGMS NIH HHS · T32 GM007739 · United States
NIAID NIH HHS · AI037526 · United States
NIAID NIH HHS · R37 AI037526 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2011.03.019 PMC Full Text View journal details
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