SCAI promotes DNA double-strand break repair in distinct chromosomal contexts

Kring Hansen, Rebecca, Mund, Andreas, Poulsen, Sara Lund, Sandoval, Maria, Klement, Karolin, Tsouroula, Katerina, Tollenaere, Maxim A X, Räschle, Markus, Soria, Rebeca, Offermanns, Stefan, Worzfeld, Thomas, Grosse, Robert, Brandt, Dominique T, Rozell,, Björn, Soutoglou, Evi and others, (2016) SCAI promotes DNA double-strand break repair in distinct chromosomal contexts. Nature Cell Biology, 18 (12). pp. 1357-1366. ISSN 1465-7392

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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 environment1,2. 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 13 Jul 2020 09:57
Last Modified: 13 Jul 2020 10:00

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