title: Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition.
abstract: Topoisomerase I (TOP1) inhibitors are an important class of anticancer drugs. The cytotoxicity of TOP1 inhibitors can be modulated by replication fork reversal through a process that requires poly(ADP-ribose) polymerase (PARP) activity. Whether regressed forks can efficiently restart and what factors are required to restart fork progression after fork reversal are still unknown. We have combined biochemical and EM approaches with single-molecule DNA fiber analysis to identify a key role for human RECQ1 helicase in replication fork restart after TOP1 inhibition that is not shared by other human RecQ proteins. We show that the poly(ADP-ribosyl)ation activity of PARP1 stabilizes forks in the regressed state by limiting their restart by RECQ1. These studies provide new mechanistic insights into the roles of RECQ1 and PARP in DNA replication and offer molecular perspectives to potentiate chemotherapeutic regimens based on TOP1 inhibition.
authors: Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Matteo
authors: M
authors: Berti
authors: Arnab
authors: A
authors: Ray Chaudhuri
authors: Saravanabhavan
authors: S
authors: Thangavel
authors: Shivasankari
authors: S
authors: Gomathinayagam
authors: Sasa
authors: S
authors: Kenig
authors: Marko
authors: M
authors: Vujanovic
authors: Federico
authors: F
authors: Odreman
authors: Timo
authors: T
authors: Glatter
authors: Simona
authors: S
authors: Graziano
authors: Ramiro
authors: R
authors: Mendoza-Maldonado
authors: Francesca
authors: F
authors: Marino
authors: Bojana
authors: B
authors: Lucic
authors: Valentina
authors: V
authors: Biasin
authors: Matthias
authors: M
authors: Gstaiger
authors: Ruedi
authors: R
authors: Aebersold
authors: Julia M
authors: JM
authors: Sidorova
authors: Raymond J
authors: RJ
authors: Monnat
authors: Massimo
authors: M
authors: Lopes
authors: Alessandro
authors: A
authors: Vindigni
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
chemical_list: D059004:Topoisomerase I Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C506725:RECQL protein, human; D053484:RecQ Helicases; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin
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