Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

Anne Bothmer, Davide F. Robbiani, Michela Di Virgilio, Samuel F. Bunting, Isaac A. Klein, Niklas Feldhahn, Jacqueline Barlow, Hua Tang Chen, David Bosque, Elsa Callen, André Nussenzweig, Michel C. Nussenzweig

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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.

Original languageEnglish (US)
Pages (from-to)319-329
Number of pages11
JournalMolecular Cell
Volume42
Issue number3
DOIs
StatePublished - May 6 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Bothmer, A., Robbiani, D. F., Di Virgilio, M., Bunting, S. F., Klein, I. A., Feldhahn, N., Barlow, J., Chen, H. T., Bosque, D., Callen, E., Nussenzweig, A., & Nussenzweig, M. C. (2011). Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1. Molecular Cell, 42(3), 319-329. https://doi.org/10.1016/j.molcel.2011.03.019