Journal
NATURE CELL BIOLOGY
Volume 18, Issue 12, Pages 1357-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3436
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Funding
- Novo Nordisk Foundation [NNF14CC0001, NNF15OC0016926]
- European Research Council (ERC)
- Danish Cancer Society
- Danish Medical Research Council
- Lundbeck Foundation
- Center for Integrated Protein Research Munich (CIPSM)
- Marie Curie Intra-European Fellowship for Career Development [627187]
- Canadian Institutes of Health Research
- Canada Research Chairs programme
- Cancer Prevention and Research Institute of Texas [R1213]
- Jeanne F. Shelby Scholarship Fund
- National Institutes of Health [DP2HD087943]
- German Research Foundation [GR 2111/2-2]
- Novo Nordisk Fonden [NNF15OC0016926] Funding Source: researchfish
- Novo Nordisk Foundation Center for Protein Research [PI Niels Mailand] Funding Source: researchfish
- The Danish Cancer Society [R124-A7677, R124-A7601] Funding Source: researchfish
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DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment(1,2). Here, we identify SCAI (suppressor of cancer cell invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs. Cells lacking SCAI display reduced DSB repair capacity, hypersensitivity to DSB-inflicting agents and genome instability. We demonstrate that SCAI is a mediator of 53BP1-dependent repair of heterochromatin-associated DSBs, facilitating ATM kinase signalling at DSBs in repressive chromatin environments. Moreover, we establish an important role of SCAI in meiotic recombination, as SCAI deficiency in mice leads to germ cell loss and subfertility associated with impaired retention of the DMC1 recombinase on meiotic chromosomes. Collectively, our findings uncover SCAI as a physiologically important component of both NHEJ-and HR-mediated pathways that potentiates DSB repair efficiency in specific chromatin contexts.
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