title: RECQ1 plays a distinct role in cellular response to oxidative DNA damage.
abstract: RECQ1 is the most abundant RecQ homolog in humans but its functions have remained mostly elusive. Biochemically, RECQ1 displays distinct substrate specificities from WRN and BLM, indicating that these RecQ helicases likely perform non-overlapping functions. Our earlier work demonstrated that RECQ1-deficient cells display spontaneous genomic instability. We have obtained key evidence suggesting a unique role of RECQ1 in repair of oxidative DNA damage. We show that similar to WRN, RECQ1 associates with PARP-1 in nuclear extracts and exhibits direct protein interaction in vitro. Deficiency in WRN or BLM helicases have been shown to result in reduced homologous recombination and hyperactivation of PARP under basal condition. However, RECQ1-deficiency did not lead to PARP activation in undamaged cells and nor did it result in reduction in homologous recombination repair. In stark contrast to what is seen in WRN-deficiency, RECQ1-deficient cells hyperactivate PARP in a specific response to H₂O₂treatment. RECQ1-deficient cells are more sensitive to oxidative DNA damage and exposure to oxidative stress results in a rapid and reversible recruitment of RECQ1 to chromatin. Chromatin localization of RECQ1 precedes WRN helicase, which has been shown to function in oxidative DNA damage repair. However, oxidative DNA damage-induced chromatin recruitment of these RecQ helicases is independent of PARP activity. As other RecQ helicases are known to interact with PARP-1, this study provides a paradigm to delineate specialized and redundant functions of RecQ homologs in repair of oxidative DNA damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, 520 W Street, NW, Washington, DC 20059, USA. sudha.sharma@howard.edu
authors.forename: Sudha
authors.initials: S
authors.lastname: Sharma
authors.forename: Pornima
authors.initials: P
authors.lastname: Phatak
authors.forename: Alexei
authors.initials: A
authors.lastname: Stortchevoi
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Jeannine R
authors.initials: JR
authors.lastname: Larocque
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D016877:Oxidants; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; C506725:RECQL protein, human; D053484:RecQ Helicases