53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.
- Ghezraoui H Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Oliveira C Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Becker JR Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Bilham K Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Moralli D Chromosome Dynamics, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Anzilotti C MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Fischer R Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Deobagkar-Lele M MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Sanchiz-Calvo M Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Fueyo-Marcos E Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Bonham S Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Kessler BM Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Rottenberg S Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
- Cornall RJ MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Green CM Chromosome Dynamics, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Chapman JR Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. rchapman@well.ox.ac.uk.
- 2018-07-27
Published in:
- Nature. - 2018
Animals
Cell Cycle Proteins
Cell Line
DNA
DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA, Single-Stranded
DNA-Binding Proteins
Female
Humans
Immunoglobulin Class Switching
Mad2 Proteins
Male
Mice
Mice, Inbred C57BL
Multiprotein Complexes
Mutation
Tumor Suppressor p53-Binding Protein 1
V(D)J Recombination
English
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1038/s41586-018-0362-1
- PMID 30046110
- Persistent URL
- https://sonar.ch/global/documents/185130
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