title: A new sub-pathway of long-patch base excision repair involving 5' gap formation.
abstract: Base excision repair (BER) is one of the most frequently used cellular DNA repair mechanisms and modulates many human pathophysiological conditions related to DNA damage. Through live cell andin vitroreconstitution experiments, we have discovered a major sub-pathway of conventional long-patch BER that involves formation of a 9-nucleotide gap 5' to the lesion. This new sub-pathway is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 poly(ADP-ribose) polymerase and RPA The novel gap formation step is employed during repair of a variety of DNA lesions, including oxidative and alkylation damage. Moreover, RECQ1 regulates PARP1 auto-(ADP-ribosyl)ation and the choice between long-patch and single-nucleotide BER, thereby modulating cellular sensitivity to DNA damage. Based on these results, we propose a revised model of long-patch BER and a new key regulation point for pathway choice in BER.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Woodrick
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Suhani
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Camacho
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Parvathaneni
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Cheema
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Khatkar
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Hayriye Verda
authors.initials: HV
authors.lastname: Erkizan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: Furqan
authors.initials: F
authors.lastname: Sami
authors.affiliation: Department of Pharmacological Sciences & Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pharmacological Sciences & Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Schärer
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA sudha.sharma@howard.edu rr228@georgetown.edu.
authors.forename: Sudha
authors.identifier: 0000-0003-2765-2482
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA sudha.sharma@howard.edu rr228@georgetown.edu.
authors.forename: Rabindra
authors.identifier: 0000-0002-9774-9012
authors.initials: R
authors.lastname: Roy
mesh_terms: D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D053484:RecQ Helicases / Q000378:metabolism*; D051716:Replication Protein A / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C497167:RPA1 protein, human; D051716:Replication Protein A; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C071447:ERCC1 protein, human; D004720:Endonucleases; C506725:RECQL protein, human; D053484:RecQ Helicases
keywords: BER pathway switch; PARP inhibition; RECQ1; XPF‐ERCC1; oxidative damage