Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency.
Single-base lesions in DNA are repaired predominantly by base excision repair (BER). DNA polymerase beta (pol beta) is the polymerase of choice in the preferred single-nucleotide BER pathway. The characteristic phenotype of mouse fibroblasts with a deletion of the pol beta gene is moderate hypersensitivity to monofunctional alkylating agents, e.g., methyl methanesulfonate (MMS). Increased sensitivity to MMS is also seen in the absence of pol beta partner proteins XRCC1 and PARP-1, and under conditions where BER efficiency is reduced by synthetic inhibitors. PARP activity plays a major role in protection against MMS-induced cytotoxicity, and cells treated with a combination of non-toxic concentrations of MMS and a PARP inhibitor undergo cell cycle arrest and die by a Chk1-dependent apoptotic pathway. Since BER-deficient cells and tumors are similarly hypersensitive to the clinically used chemotherapeutic methylating agent temozolomide, modulation of DNA damage-induced cell signaling pathways, as well as BER, are attractive targets for potentiating chemotherapy.
Horton
Julie K
JK
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Wilson
Samuel H
SH
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D049914:DNA Repair-Deficiency Disorders / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D010641:Phenotype; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology
D018906:Antineoplastic Agents, Alkylating; D008741:Methyl Methanesulfonate; D011065:Poly(ADP-ribose) Polymerases; D019951:DNA Polymerase beta; D045643:DNA Repair Enzymes