TY - JOUR
T1 - SCAI promotes DNA double-strand break repair in distinct chromosomal contexts
AU - Hansen, Rebecca Kring
AU - Mund, Andreas
AU - Poulsen, Sara Lund
AU - Sandoval, Maria
AU - Klement, Karolin
AU - Tsouroula, Katerina
AU - Tollenaere, Maxim A.X.
AU - Räschle, Markus
AU - Soria, Rebeca
AU - Oermanns, Stefan
AU - Worzfeld, Thomas
AU - Grosse, Robert
AU - Brandt, Dominique T.
AU - Rozell, Björn
AU - Mann, Matthias
AU - Cole, Francesca
AU - Soutoglou, Evi
AU - Goodarzi, Aaron A.
AU - Daniel, Jeremy A.
AU - Mailand, Niels
AU - Bekker-Jensen, Simon
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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. 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.
AB - 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. 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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U2 - 10.1038/ncb3436
DO - 10.1038/ncb3436
M3 - Article
C2 - 27820601
AN - SCOPUS:84994608201
SN - 1465-7392
VL - 18
SP - 1357
EP - 1366
JO - Nature cell biology
JF - Nature cell biology
IS - 12
ER -