DNA glycosylase encoded by MUTYH functions as a molecular switch for programmed cell death under oxidative stress to suppress tumorigenesis

Sugako Oka, Yusaku Nakabeppu

Research output: Contribution to journalReview article

40 Citations (Scopus)

Abstract

8-oxoguanine is a major base lesion in DNA or in nucleotides caused by oxidative stress, and is highly mutagenic because it can pair with adenine as well as cytosine. Adenine DNA glycosylase, encoded by the human mutY homolog gene, MUTYH, excises adenine in the nascent strand when inserted opposite 8-oxoguanine in template DNA, and thus suppresses mutagenesis caused by 8-oxoguanine that has accumulated in DNA due to oxidative stress. Several germ-line mutations in MUTYH are predisposed to MUTYH-associated polyposis, an autosomal recessive disorder characterized by multiple colorectal adenomas and carcinomas. Loss of function of MUTYH leads to an accumulation of somatic mutations in APC and KRAS genes, resulting in the development of adenomas/carcinomas. We recently demonstrated that accumulation of 8-oxoguanine in nuclear and mitochondrial DNA triggers two distinct cell death pathways that are independent of each other. Both pathways are initiated by the accumulation of MUTYH-generated single-strand breaks (SSBs) in nuclear or mitochondrial DNA. Our findings indicate that MUTYH-induced cell death due to oxidative stress results in an efficient elimination of mutagenic cells that have accumulated high levels of 8-oxoguanine in their DNAs. It is most likely that loss of function of MUTYH in stem or progenitor cells in the intestinal epithelium of MUTYH-associated polyposis patients results in escape from programmed cell death; however, accumulated 8-oxoguanine causes various mutations in APC or KRAS genes in these proliferative cells, thereby promoting tumorigenesis. We thus propose that MUTYH suppresses tumorigenesis under conditions of oxidative stress by inducing cell death and by suppressing mutagenesis.

Original languageEnglish
Pages (from-to)677-682
Number of pages6
JournalCancer Science
Volume102
Issue number4
DOIs
Publication statusPublished - Apr 1 2011

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DNA Glycosylases
Carcinogenesis
Oxidative Stress
Cell Death
DNA
Adenine
Mitochondrial DNA
Mutagenesis
Adenoma
Stem Cells
APC Genes
Germ-Line Mutation
Cytosine
Intestinal Mucosa
Genes
8-hydroxyguanine
Colorectal Neoplasms
Nucleotides
Carcinoma
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

DNA glycosylase encoded by MUTYH functions as a molecular switch for programmed cell death under oxidative stress to suppress tumorigenesis. / Oka, Sugako; Nakabeppu, Yusaku.

In: Cancer Science, Vol. 102, No. 4, 01.04.2011, p. 677-682.

Research output: Contribution to journalReview article

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