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Nature. 2018 Aug;560(7716):122-127. doi: 10.1038/s41586-018-0362-1. Epub 2018 Jul 25.

53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.

Author information

1
Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
2
Chromosome Dynamics, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
3
MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
4
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
5
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
6
Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. rchapman@well.ox.ac.uk.

Abstract

53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination1,2, and reduced fidelity of long-range V(D)J recombination3. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres4, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis5-7. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive8, unlike 53BP1-deficient cells9,10, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin-a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)-as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.

PMID:
30046110
DOI:
10.1038/s41586-018-0362-1
[Indexed for MEDLINE]

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