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

Abstract

V(D)J recombination and class switch recombination employ overlapping but distinct non-homologous end-joining (NHEJ) pathways to repair DNA double strand break (DSB) intermediates. 53BP1 is a DNA damage response protein that is rapidly recruited to sites of chromosomal DSBs, where it appears to function in a subset of ataxia-telangiectasia mutated (ATM) kinase, H2AX- and 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 recombination CSR3, 4. Here, we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1 deficient lymphocytes distinct from that found in classical NHEJ-, H2AX-, MDC1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of un-repaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes bearing antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long range joining of DNA breaks.

IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

“…The mechanistic driver of IgD CSR in the 53BP1-deficient state and in other mutant mice lacking cCSR remains unknown. We noticed that a commonality in 53BP1 and 3′RR deficiency is a failure to support proper synapsis of DSB ends (11,12,20), which may permit DNA end resection leading to HR. A corollary is that deficiency of H2AX, another suppressor of DNA end resection (21,22), might result in a mechanistically similar hyper-IgD phenotype.…”

“…Hyperactivation of this pathway in 53BP1-deficient mice may be a compensatory response to the lack of antibody isotypes normally produced by cCSR, and thus may confer a protective effect. Unlike cCSR (5, 18), S μ -σ δ CSR is functional in the absence of 53BP1, possibly because 53BP1 may be dispensable for short-range DNA endjoining (11,12). 53BP1 is known to block DNA end resection and thereby promote NHEJ during cCSR; conversely, intraswitch recombination via HR is favored in the 53BP1-deficient state (13,19).…”

“…Taken together, these data demonstrate that 53BP1 deficiency results in a loss of cCSR with a concomitant increase in AID-dependent S μ -σ δ CSR at defined anatomic sites that more than compensates for the loss of cCSR. In the absence of 53BP1, AID-mediated DNA DSBs at the Igh locus are repaired by ATM-dependent alternative nonhomologous end-joining (A-NHEJ; suppressed by canonical NHEJ) in the G1 phase or by homologous recombination (HR) in the S-G2/M phase of the cell cycle (10)(11)(12)(13). Extensive DNA template resection in HR inhibits ATM activity and reduces the formation of chromosomal translocations via A-NHEJ (14).…”

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…The absence of 53BP1 in mice leads to impairment of distal V(D)J joining with extensive degradation of unrepaired coding ends and episomal signal joint re‐integration at V(D)J junctions. This results in apoptosis, loss of TCRα locus integrity and lymphopenia 53. However, others report that the defect of 53BP1‐deficient mice in V(D)J recombination is only mild54 and to date no human mutation in this gene has been reported.…”

53BP1 represses mitotic catastrophe in syncytia elicited by the HIV-1 envelope

“…Originally described as 53BP1, it is currently considered as a major initiator of DNA damage signaling and/or repair. [14][15][16][17][18] Normally diffusely distributed through the nucleus during interphase, 53BP1 is recruited to sites of DNA lesions upon DDR 19,20 in which it interacts with DNA double-strand breaks and many proteins involved in DNA damage, repair and checkpoint signaling, including BRCA1, Rad51, Mre11/Rad50/NBS1, ATM and g-H2AX, to constitute DNA damage-inducible foci. 15,[21][22][23] Upon DDR, 53BP1 becomes hyper-phosphorylated (on serines 25 and 1778) in an ATM-dependent manner.…”