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

Xin Sun, Kai Fu, Andrea Hodgson, Eric M. Wier, Matthew G. Wen, Olena Kamenyeva, Xue Xia, Lily Y. Koo, Fengyi Wan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1002543
JournalPLoS biology
Volume14
Issue number9
DOIs
StatePublished - Sep 16 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Sun, X., Fu, K., Hodgson, A., Wier, E. M., Wen, M. G., Kamenyeva, O., Xia, X., Koo, L. Y., & Wan, F. (2016). Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation. PLoS biology, 14(9), [e1002543]. https://doi.org/10.1371/journal.pbio.1002543