Exposure to environmental mutagens: APC and colorectal carcinogenesis

Aruna S. Jaiswal, Melissa L. Armas, Shahnjayla K. Connors, Harekrushna Panda, Satya Narayan

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Environmental mutagens are global health hazards and a major risk factor for colon cancer development. Environmental mutagens include a variety of genotoxic carcinogenic compounds including polycyclic aromatic hydrocarbons, heterocyclic amines, nitrosamines, and aromatic amines. Their sources are pollution, diet, alcohol and cigarette smoke. These mutagens come in contact with large bowel through blood circulation or direct ingestion. Once these mutagens are in contact with DNA of the gut epithelial cells, they form DNA-adducts. If the damage exceeds the repair capacity of the epithelial cells, then the persistence of mutations can lead to the transformation of these cells. Mutations in adenomatous polyposis coli (APC) gene is considered to be one of the earliest events in the genesis of colorectal cancer, and its role has been well documented in a broad spectrum of functions ranging from cell adhesion to cell migration, regulation of Wnt/β-catenin-signaling pathway, cell cycle control, apoptosis, and chromosomal segregation at mitosis. The contribution of environmental mutagens on the APC gene mutations is very scanty in the literature. In the past several years, we have initiated studies to examine the interaction of APC with pathways induced by environmental mutagens. We showed that APC can be transcriptionally upregulated after DNA damage subsequent to the exposure of environmental mutagens including cigarette smoking. In addition, we recently discovered a novel role of APC in base excision repair (BER) pathway. APC interacts with DNA polymerase β and Fen-1 and blocks Pol-β-directed BER. Thus, APC-mediated block of BER in response to environmental mutagens, especially the DNA-alkylating agents, can be detrimental to the cell.

Original languageEnglish (US)
Title of host publicationEnvironmental Factors, Genes, and the Development of Human Cancers
PublisherSpringer New York
Pages303-329
Number of pages27
ISBN (Print)9781441967510
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Keywords

  • Adenomatous polyposis coli
  • Colorectal carcinogenesis
  • DNA damage
  • DNA repair
  • Environmental mutagens

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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