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Gastric cancer associated variant of DNA polymerase beta (Leu22Pro) promotes DNA replication associated double strand breaks.

Title: Gastric cancer associated variant of DNA polymerase beta (Leu22Pro) promotes DNA replication associated double strand breaks.
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Name(s): Rozacky, Jenna, author
Nemec, Antoni A, author
Sweasy, Joann B, author
Kidane, Dawit, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2015-09-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_26090616 (IID), 10.18632/oncotarget.4426 (DOI), PMC4695199 (PMCID), 26090616 (RID), 26090616 (EID), 4426 (PII)
Keywords: DNA polymerase beta, Gastric cancer
Grant Number: K01 CA15485401
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695199.
Subject(s): Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA Polymerase beta/genetics
DNA Repair/genetics
DNA Replication/genetics
DNA, Single-Stranded/genetics
Humans
Phosphorus-Oxygen Lyases/genetics
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
Poly(ADP-ribose) Polymerases/metabolism
Protein Isoforms/genetics
Rad51 Recombinase/biosynthesis
Stomach Neoplasms/genetics
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26090616
Owner Institution: FSU
Is Part Of: Oncotarget.
1949-2553
Issue: iss. 27, vol. 6

Choose the citation style.
Rozacky, J., Nemec, A. A., Sweasy, J. B., & Kidane, D. (2015). Gastric cancer associated variant of DNA polymerase beta (Leu22Pro) promotes DNA replication associated double strand breaks. Oncotarget. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26090616