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

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Abstract
When either exogenous or endogenous double-strand breaks occur, the p53 binding protein 53BP1 is one of the earliest proteins to be recruited to the site of the break. 53BP1 helps to promote rejoining of DNA ends during class switch recombination; in a pair of papers in this week's Nature, the laboratories of André Nussenzweig and Titia de Lange show it is also required for V(D)J recombination and for joining of DNA breaks in telomeres. In V(D)J recombination, the ends of the programmed double-strand break are degraded when 53BP1 is absent, and joining between distal V and DJ segments is affected. At broken telomeres, 53BP1 increases the volume of the nucleus searched by the DNA ends so that they are more likely to encounter a partner to which they can be ligated. Thus, 53BP1 facilitates repair by changing the dynamics of movement of broken ends, making long-range interactions more frequent. 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, is reported. 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 events1,2. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination3,4. 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.