Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation.

Autor: Sun X; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Fu K; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Hodgson A; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Wier EM; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Wen MG; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Kamenyeva O; Biological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America., Xia X; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America., Koo LY; Biological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America., Wan F; 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.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2016 Sep 16; Vol. 14 (9), pp. e1002543. Date of Electronic Publication: 2016 Sep 16 (Print Publication: 2016).
DOI: 10.1371/journal.pbio.1002543
Abstrakt: 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.
Competing Interests: No.
Databáze: MEDLINE
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