title: The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage.
abstract: The list of factors that participate in the DNA damage response to maintain genomic stability has expanded significantly to include a role for proteins involved in RNA processing. Here, we provide evidence that the RNA-binding protein fused in sarcoma/translocated in liposarcoma (FUS) is a novel component of the DNA damage response. We demonstrate that FUS is rapidly recruited to sites of laser-induced DNA double-strand breaks (DSBs) in a manner that requires poly(ADP-ribose) (PAR) polymerase activity, but is independent of ataxia-telangiectasia mutated kinase function. FUS recruitment is mediated by the arginine/glycine-rich domains, which interact directly with PAR. In addition, we identify a role for the prion-like domain in promoting accumulation of FUS at sites of DNA damage. Finally, depletion of FUS diminished DSB repair through both homologous recombination and nonhomologous end-joining, implicating FUS as an upstream participant in both pathways. These results identify FUS as a new factor in the immediate response to DSBs that functions downstream of PAR polymerase to preserve genomic integrity.
authors.affiliation: Department of Human Oncology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Mastrocola
authors.forename: Sang Hwa
authors.initials: SH
authors.lastname: Kim
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Trinh
authors.forename: Lance A
authors.initials: LA
authors.lastname: Rodenkirch
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D007834:Lasers / Q000009:adverse effects; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*
chemical_list: D034702:RNA-Binding Protein FUS; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases
keywords: ATM; DNA Damage Response; DNA Repair; Fused in Sarcoma; Homologous Recombination; PARP; RNA-binding Proteins; Radiation Biology