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

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 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.

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Figure 1: Antigen-receptor-associated aberrations in 53BP1 -/- lymphocytes.
Figure 2: Processing of Jα coding ends in 53BP1-deficient thymocytes.
Figure 3: Decreased efficiency of long-range V(D)J recombination and Tcra locus contraction in 53BP1 -/- thymocytes.
Figure 4: Model for the role of 53BP1 in promoting and/or maintaining synapsis during V(D)J recombination.

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Acknowledgements

We are grateful to M. McAuliffe and co-workers for developing the three-dimensional-FISH measurement algorithm; D. G. Schatz and J. Haber for discussions; A. Wynshaw-Boris for Atm-/- mice and J. Chen for 53BP1-/- and Mdc1-/- mice; D. Venzon for help with statistical analysis; and members of the A. Nussenzweig laboratory (J. Daniel and A. Celeste) for comments on the manuscript. B.P.S. is supported by NIH grant R01AI074953. E.G. is supported by pre-doctoral fellowship from the Cancer Research Institute. M.C.N. is a HHMI investigator. A.N. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Correspondence to André Nussenzweig.

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Difilippantonio, S., Gapud, E., Wong, N. et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456, 529–533 (2008). https://doi.org/10.1038/nature07476

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