MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death

Research output: Contribution to journalArticle

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Abstract

p53-regulated caspase-independent cell death has been implicated in suppression of tumorigenesis, however, the regulating mechanisms are poorly understood. We previously reported that 8-oxoguanine (8-oxoG) accumulation in nuclear DNA (nDNA) and mitochondrial DNA triggers two distinct caspase-independent cell death through buildup of single-strand DNA breaks by MutY homolog (MUTYH), an adenine DNA glycosylase. One pathway depends on poly-ADP-ribose polymerase (PARP) and the other depends on calpains. Deficiency of MUTYH causes MUTYH-associated familial adenomatous polyposis. MUTYH thereby suppresses tumorigenesis not only by avoiding mutagenesis, but also by inducing cell death. Here, we identified the functional p53-binding site in the human MUTYH gene and demonstrated that MUTYH is transcriptionally regulated by p53, especially in the p53/DNA mismatch repair enzyme, MLH1-proficient colorectal cancer-derived HCT116+Chr3 cells. MUTYH-small interfering RNA, an inhibitor for p53 or PARP suppressed cell death without an additive effect, thus revealing that MUTYH is a potential mediator of p53 tumor suppression, which is known to be upregulated by MLH1. Moreover, we found that the p53-proficient, mismatch repair protein, MLH1-proficient colorectal cancer cell line express substantial levels of MUTYH in nuclei but not in mitochondria, suggesting that 8- oxoG accumulation in nDNA triggers MLH1/PARP-dependent cell death. These results provide new insights on the molecular mechanism of tumorigenesis and potential new strategies for cancer therapies

Original languageEnglish
Article numbere121
JournalOncogenesis
Volume3
Issue number10
DOIs
Publication statusPublished - Jan 1 2014

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DNA Glycosylases
Poly(ADP-ribose) Polymerases
Cell Death
Carcinogenesis
DNA Mismatch Repair
Neoplasms
Caspases
Colorectal Neoplasms
DNA Repair Enzymes
HCT116 Cells
Single-Stranded DNA Breaks
Adenomatous Polyposis Coli
Calpain
DNA
Mitochondrial DNA
Mutagenesis
Small Interfering RNA
Mitochondria
Binding Sites
adenine glycosylase

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death. / Oka, S.; Leon, J.; Tsuchimoto, Daisuke; Kunihiko, Sakumi; Nakabeppu, Yusaku.

In: Oncogenesis, Vol. 3, No. 10, e121, 01.01.2014.

Research output: Contribution to journalArticle

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