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

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 - Offermanns, 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

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.

U2 - 10.1038/ncb3436

DO - 10.1038/ncb3436

M3 - Letter

C2 - 27820601

SN - 1465-7392

VL - 18

SP - 1357

EP - 1366

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 12

ER -