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

J Biol Chem. 2005 Feb 25;280(8):6942-9. doi: 10.1074/jbc.M409200200. Epub 2004 Nov 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Adenomatous Polyposis Coli Protein / physiology*
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Colonic Neoplasms / pathology
  • DNA / biosynthesis*
  • DNA Methylation
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Polymerase beta / metabolism
  • DNA Repair*
  • Embryo, Mammalian / cytology
  • Humans
  • Methyl Methanesulfonate / pharmacology*
  • Mice
  • Mice, Knockout
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / metabolism
  • Tumor Suppressor Proteins / physiology
  • Two-Hybrid System Techniques

Substances

  • Adenomatous Polyposis Coli Protein
  • Peptide Fragments
  • Tumor Suppressor Proteins
  • DNA
  • Methyl Methanesulfonate
  • DNA Polymerase beta