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

S Oka1, J Leon2, D Tsuchimoto1

  • 11] Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan [2] Research Center for Nucleotide Pool, Kyushu University, Fukuoka, Japan.

Oncogenesis
|October 14, 2014
PubMed

Insights

MutY homolog (MUTYH) induces caspase-independent cell death, suppressing tumors. p53 regulates MUTYH, linking it to tumor suppression pathways involving DNA repair and cell death.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • p53-regulated caspase-independent cell death is crucial for tumor suppression but its mechanisms are unclear.
  • 8-oxoguanine (8-oxoG) accumulation triggers distinct cell death pathways mediated by MUTYH.
  • MUTYH deficiency is linked to familial adenomatous polyposis, highlighting its role in suppressing tumorigenesis.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of p53-mediated caspase-independent cell death.
  • To identify the functional p53-binding site in the human MUTYH gene.
  • To investigate MUTYH's role as a mediator of p53 tumor suppression.

Main Methods:

  • Identification of the p53-binding site in the human MUTYH gene.
  • Assessment of MUTYH's transcriptional regulation by p53 in colorectal cancer cells (HCT116+Chr3).
  • Experimental manipulation using MUTYH-small interfering RNA, p53 inhibitors, and PARP inhibitors to study cell death pathways.

Main Results:

  • MUTYH is transcriptionally regulated by p53, particularly in MLH1-proficient colorectal cancer cells.
  • Inhibition of MUTYH, p53, or PARP suppressed cell death without additive effects, confirming MUTYH's mediator role.
  • p53-proficient, MLH1-proficient cells show nuclear MUTYH, suggesting nuclear 8-oxoG accumulation triggers MLH1/PARP-dependent cell death.

Conclusions:

  • MUTYH acts as a mediator of p53 tumor suppression through transcriptional regulation.
  • The study reveals a novel molecular mechanism linking 8-oxoG accumulation, DNA repair (MUTYH, MLH1, PARP), and cell death in tumorigenesis.
  • Findings offer potential new strategies for cancer therapy targeting these pathways.

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