Base Excision Repair Defects Invoke Hypersensitivity to PARP Inhibition
| Autor: | Julie K. Horton, Donna F. Stefanick, Natalie R. Gassman, Padmini S. Kedar, Samuel H. Wilson, Rajendra Prasad |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
DNA Repair Veliparib DNA polymerase DNA damage DNA repair Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor Article Cell Line Mice XRCC1 chemistry.chemical_compound Animals DNA Breaks Double-Stranded Enzyme Inhibitors Molecular Biology biology DNA Base excision repair Molecular biology DNA-Binding Proteins X-ray Repair Cross Complementing Protein 1 Oncology chemistry PARP inhibitor biology.protein Poly(ADP-ribose) Polymerases DNA Damage |
| Zdroj: | Molecular Cancer Research. 12:1128-1139 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-13-0502 |
| Popis: | PARP-1 is important for the recognition of both endogenous and exogenous DNA damage, and binds to DNA strand breaks including intermediates of base excision repair (BER). Once DNA-bound, PARP-1 becomes catalytically activated synthesizing PAR polymers onto itself and other repair factors (PARylation). As a result, BER repair proteins such as XRCC1 and DNA polymerase β (pol β) are more efficiently and rapidly recruited to sites of DNA damage. In the presence of an inhibitor of PARP activity (PARPi), PARP-1 binds to sites of DNA damage, but PARylation is prevented. BER enzyme recruitment is hindered, but binding of PARP-1 to DNA is stabilized, impeding DNA repair and leading to double-strand DNA breaks (DSB). Deficiencies in pol β−/− and Xrcc1−/− cells resulted in hypersensitivity to the PARP inhibitor 4-AN and reexpression of pol β or XRCC1, in these contexts, reversed the 4-AN hypersensitivity phenotype. BER deficiencies also showed evidence of replication defects that lead to DSB-induced apoptosis upon PARPi treatment. Finally, the clinically relevant PARP inhibitors olaparib and veliparib also exhibited hypersensitivity in both pol β−/− and Xrcc1−/− BER-deficient cells. These results reveal heightened sensitivity to PARPi as a function of BER deficiency. Implications: BER deficiency represents a new therapeutic opportunity to enhance PARPi efficacy. Visual Overview: http://mcr.aacrjournals.org/content/12/8/1128/F1.large.jpg. Mol Cancer Res; 12(8); 1128–39. ©2014 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|