MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links.
MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40(-/-) mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)-BRCA ICL repair network.
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Qinqin
Q
Jiang
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA;
Manikandan
M
Paramasivam
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Bernadette
B
Aressy
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Junmin
J
Wu
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA;
Marina
M
Bellani
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Wei
W
Tong
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA;
Michael M
MM
Seidman
Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Roger A
RA
Greenberg
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D043171:Chromosomal Instability / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D056488:Histone Chaperones; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D056488:Histone Chaperones; C000598769:MERIT40 protein, mouse; C543502:Rap80 protein, mouse; D014157:Transcription Factors; D004265:DNA Helicases
BRCA2; DNA2; MERIT40; interstrand cross-link repair; ubiquitination