Tumor suppressor APC blocks DNA polymerase beta-dependent strand displacement synthesis during long patch but not short patch base excision repair and increases sensitivity to methylmethane sulfonate.
In the present investigation, we report a previously unsuspected function of the tumor suppressor protein, APC (adenomatous polyposis coli), 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 APC 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.
Narayan
Satya
S
Department of Anatomy and Cell Biology and Shands Cancer Center, University of Florida, Gainesville, Florida 32610, USA. snarayan@ufscc.ufl.edu
Jaiswal
Aruna S
AS
Balusu
Ramesh
R
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology; D004247:DNA / Q000096:biosynthesis*; D019175:DNA Methylation; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004260:DNA Repair; D004622:Embryo, Mammalian / Q000166:cytology; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology; D020798:Two-Hybrid System Techniques
D025601:Adenomatous Polyposis Coli Protein; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; D004247:DNA; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta