Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 8, Pages 6942-6949Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M409200200
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Funding
- NCI NIH HHS [R01-CA 100247, R01-CA 097031, R01 CA100247, R01 CA097031] Funding Source: Medline
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In the present investigation, we report a previously unsuspected function of the tumor suppressor protein, APC ((a) under bar denomatous (p) under bar olyposis (c) under bar oli), in the regulation of base excision repair (BER). We identified a proliferating cell nuclear antigen-interacting protein-like box sequence in APC that binds DNA polymerase beta and blocks DNA polymerase beta-mediated strand-displacement synthesis in long patch BER without affecting short patch BER. We further showed that the colon cancer cell line expressing the wild-type APC gene was more sensitive to a DNA-methylating agent due to decreased DNA repair by long patch BER than the cell line expressing the mutant A-PC gene lacking the proliferating cell nuclear antigen-interacting protein-like box. Experiments based on RNA interference showed that the wild-type APC gene expression is required for DNA methylation-induced sensitivity of colon cancer cells. Thus, APC may play a critical role in determining utilization of long versus short patch BER pathways and affect the susceptibility of colon cancer cells to carcinogenic and chemotherapeutic agents.
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