title: Differential and Concordant Roles for Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribose) in Regulating WRN and RECQL5 Activities.
abstract: Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) catalyzes the poly(ADP-ribosyl)ation (PARylation) of proteins, a posttranslational modification which forms the nucleic acid-like polymer PAR. PARP1 and PAR are integral players in the early DNA damage response, since PARylation orchestrates the recruitment of repair proteins to sites of damage. Human RecQ helicases are DNA unwinding proteins that are critical responders to DNA damage, but how their recruitment and activities are regulated by PARPs and PAR is poorly understood. Here we report that all human RecQ helicases interact with PAR noncovalently. Furthermore, we define the effects that PARP1, PARylated PARP1, and PAR have on RECQL5 and WRN, using both in vitro and in vivo assays. We show that PARylation is involved in the recruitment of RECQL5 and WRN to laser-induced DNA damage and that RECQL5 and WRN have differential responses to PARylated PARP1 and PAR. Furthermore, we show that the loss of RECQL5 or WRN resulted in increased sensitivity to PARP inhibition. In conclusion, our results demonstrate that PARP1 and PAR actively, and in some instances differentially, regulate the activities and cellular localization of RECQL5 and WRN, suggesting that PARylation acts as a fine-tuning mechanism to coordinate their functions in time and space during the genotoxic stress response.
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Prabhat
authors.initials: P
authors.lastname: Khadka
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Hsu
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Veith
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tadokoro
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Raghavendra A
authors.initials: RA
authors.lastname: Shamanna
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, Maryland, USA vbohr@nih.gov.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004789:Enzyme Activation / Q000187:drug effects; D005090:Exodeoxyribonucleases / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D060066:Protein Interaction Maps; D053484:RecQ Helicases / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C506732:RECQL5 protein, human; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005090:Exodeoxyribonucleases; D000251:Adenosine Triphosphatases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase