53BP1 facilitates long-range DNA end-joining during V(D)J recombination

Simone Difilippantonio, Eric Gapud, Nancy Wong, Ching Yu Huang, Grace Mahowald, Hua Tang Chen, Michael J. Kruhlak, Elsa Callen, Ferenc Livak, Michel C. Nussenzweig, Barry P. Sleckman, André Nussenzweig

Research output: Contribution to journalArticlepeer-review

Abstract

Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor α locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.

Original languageEnglish (US)
Pages (from-to)529-533
Number of pages5
JournalNature
Volume456
Issue number7221
DOIs
StatePublished - Nov 27 2008
Externally publishedYes

ASJC Scopus subject areas

  • General

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