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

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(1,2). A 53BP1- dependent end- joining pathway has been described that is dispensable for V( D) J recombination but essential for class- switch recombination(3,4). 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 a 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.