title: Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation.
abstract: The rapid and robust synthesis of polymers of adenosine diphosphate (ADP)-ribose (PAR) chains, primarily catalyzed by poly(ADP-ribose) polymerase 1 (PARP1), is crucial for cellular responses to DNA damage. However, the precise mechanisms through which PARP1 is activated and PAR is robustly synthesized are not fully understood. Here, we identified Src-associated substrate during mitosis of 68 kDa (Sam68) as a novel signaling molecule in DNA damage responses (DDRs). In the absence of Sam68, DNA damage-triggered PAR production and PAR-dependent DNA repair signaling were dramatically diminished. With serial cellular and biochemical assays, we demonstrated that Sam68 is recruited to and significantly overlaps with PARP1 at DNA lesions and that the interaction between Sam68 and PARP1 is crucial for DNA damage-initiated and PARP1-conferred PAR production. Utilizing cell lines and knockout mice, we illustrated that Sam68-deleted cells and animals are hypersensitive to genotoxicity caused by DNA-damaging agents. Together, our findings suggest that Sam68 plays a crucial role in DDR via regulating DNA damage-initiated PAR production.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hodgson
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wier
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Wen
authors.affiliation: Biological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Olena
authors.initials: O
authors.lastname: Kamenyeva
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Xue
authors.initials: X
authors.lastname: Xia
authors.affiliation: Biological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Koo
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Fengyi
authors.identifier: 0000-0001-9216-9767
authors.initials: F
authors.lastname: Wan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004789:Enzyme Activation; D006801:Humans; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000502:physiology*; D011833:Radiation Injuries, Experimental / Q000201:enzymology; D015398:Signal Transduction; D013950:Thymus Gland / Q000201:enzymology / Q000528:radiation effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513253:Khdrbs1 protein, mouse; D016601:RNA-Binding Proteins; D000244:Adenosine Diphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1