title: Gastric cancer associated variant of DNA polymerase beta (Leu22Pro) promotes DNA replication associated double strand breaks.
abstract: DNA polymerase beta (Pol β) is a key enzyme for the protection against oxidative DNA lesions via its role in base excision repair (BER). Approximately 1/3 of tumors studied to date express Pol β variant proteins, and several tumors overexpress Pol β. Pol β possesses DNA polymerase and dRP lyase activities, both of which are known to be important for efficient BER. The dRP lyase activity resides within the 8kDa amino terminal domain of Pol β, is responsible for removal of the 5' phosphate group (5'-dRP). The DNA polymerase subsequently fills the gaps. Previously, we demonstrated that the human gastric cancer-associated variant of Pol β (Leu22Pro (L22P)) lacks dRP lyase function in vitro. Here, we report that L22P-expressing cells harbor significantly increased replication associated DNA double strand breaks (DSBs) and defective maintenance of the nascent DNA strand (NDS) during replication stress. Moreover, L22P-expressing cells are sensitive to PARP1 inhibitors, which suggests trapped PARP1 binds to the 5'-dRP group and blocks replications forks, resulting in fork collapse and DSBs. Our data suggest that the normal function of the dRP lyase is critical to maintain replication fork integrity and prevent replication fork collapse to DSBs and cellular transformation.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Rozacky
authors.affiliation: Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA.
authors.forename: Antoni A
authors.initials: AA
authors.lastname: Nemec
authors.affiliation: Departments of Therapeutic Radiology and Genetics, The Yale Comprehensive Cancer Center, New Haven CT, USA.
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
authors.forename: Dawit
authors.initials: D
authors.lastname: Kidane
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D019951:DNA Polymerase beta / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004277:DNA, Single-Stranded / Q000235:genetics; D006801:Humans; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D051135:Rad51 Recombinase / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D004277:DNA, Single-Stranded; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020033:Protein Isoforms; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C423906:5'-deoxyribose phosphate lyase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D019951:DNA Polymerase beta; D019761:Phosphorus-Oxygen Lyases
keywords: DNA polymerase beta; gastric cancer