SCAI promotes DNA double-strand break repair in distinct chromosomal contexts.
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.
Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Rebecca Kring
RK
Hansen
Chromatin Structure and Function Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Andreas
A
Mund
Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Sara Lund
SL
Poulsen
Epigenetics and Molecular Carcinogenesis Department, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
Maria
M
Sandoval
Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry &Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Karolin
K
Klement
Institut de Génétique et de Biologie Moléculaire et Celullaire (IGBMC), University of Strasbourg, 67404 Illkirch, France.
Katerina
K
Tsouroula
Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.|Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Maxim A X
MA
Tollenaere
Department of Molecular Genetics, TU Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany.
Markus
http://orcid.org/0000-0002-6737-7203
M
Räschle
Chromatin Structure and Function Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Rebeca
R
Soria
Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, 61231 Bad Nauheim, Germany.
Stefan
S
Offermanns
Max-Planck-Institute for Heart and Lung Research, Department of Pharmacology, 61231 Bad Nauheim, Germany.|Institute of Pharmacology, University of Marburg, 35032 Marburg, Germany.
Thomas
T
Worzfeld
Institute of Pharmacology, University of Marburg, 35032 Marburg, Germany.
Robert
http://orcid.org/0000-0002-3380-5273
R
Grosse
Institute of Pharmacology, University of Marburg, 35032 Marburg, Germany.
Dominique T
DT
Brandt
Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Björn
B
Rozell
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Matthias
M
Mann
Epigenetics and Molecular Carcinogenesis Department, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
Francesca
F
Cole
Institut de Génétique et de Biologie Moléculaire et Celullaire (IGBMC), University of Strasbourg, 67404 Illkirch, France.
Evi
E
Soutoglou
Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry &Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Aaron A
AA
Goodarzi
Chromatin Structure and Function Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Jeremy A
JA
Daniel
Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Niels
http://orcid.org/0000-0002-6623-709X
N
Mailand
Ubiquitin Signaling Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.|Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Simon
S
Bekker-Jensen
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D033481:Chromosomes, Mammalian / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D008540:Meiosis; D051379:Mice; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism*; D014981:Xenopus
D006570:Heterochromatin; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; D049452:Green Fluorescent Proteins; D064007:Ataxia Telangiectasia Mutated Proteins