title: The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair.
abstract: BRCA1 and BRCA2 are essential for the repair of double-strand DNA breaks, and alterations in these genes are a hallmark of breast and ovarian carcinomas. Other functionally related genes may also play important roles in carcinogenesis. Amplification of EMSY, a putative BRCAness gene, has been suggested to impair DNA damage repair by suppressing BRCA2 function. We employed direct repeat GFP (DR-GFP) and RAD51 foci formation assays to show that EMSY overexpression impairs the repair of damaged DNA, suggesting that EMSY belongs to the family of BRCAness proteins. We also identified a novel phospho-site at threonine 207 (T207) and demonstrated its role in EMSY-driven suppression of DNA damage repair. In vitro kinase assays established that protein kinase A (PKA) directly phosphorylates the T207 phospho-site. Immunoprecipitation experiments suggest that EMSY-driven suppression of DNA damage repair is a BRCA2-independent process. The data also suggest that EMSY amplification is a BRCAness feature, and may help to expand the population of patients who could benefit from targeted therapies that are also effective in BRCA1/2-mutant cancers.
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Jelinic
authors.affiliation: Departments of Radiation Oncology and Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Eccles
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Tseng
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Paulina
authors.initials: P
authors.lastname: Cybulska
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA.
authors.forename: Monicka
authors.initials: M
authors.lastname: Wielgos
authors.affiliation: Departments of Radiation Oncology and Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, Division of Gynecologic Oncology, Department of OB/GYN, NYU Langone Medical Center, New York, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism
chemical_list: C480344:EMSY protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D013912:Threonine
keywords: BRCA2; BRCAness; DNA repair; EMSY; PKA