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Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway

Margareta T Wilhelm1, Alessandro Rufini, Monica K Wetzel

  • 1The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada.

Genes & Development
|March 3, 2010
PubMed

Insights

The tumor suppressor p73

Area of Science:

  • Molecular Biology
  • Genetics
  • Neuroscience

Background:

  • The p73 gene encodes multiple isoforms, including TAp73 and DeltaNp73.
  • Complete p73 deficiency in mice leads to severe neurological and immunological defects.
  • The specific roles of individual p73 isoforms remain incompletely understood.

Purpose of the Study:

  • To investigate the specific biological functions of the DeltaNp73 isoform.
  • To elucidate the role of DeltaNp73 in the DNA damage response pathway.

Main Methods:

  • Generation and analysis of mice selectively deficient for DeltaNp73 (DeltaNp73(-/-) mice).
  • Assessment of neurodegeneration, DNA damage sensitivity, and apoptosis in DeltaNp73(-/-) cells.
  • Investigation of the DNA damage response (DDR) pathway, including protein interactions and signaling.

Main Results:

  • DeltaNp73(-/-) mice are viable and fertile but exhibit neurodegeneration.
  • Cells lacking DeltaNp73 show increased sensitivity to DNA-damaging agents and enhanced p53-dependent apoptosis.
  • DeltaNp73 was found to inhibit the DNA damage response by localizing to DNA breaks, interacting with 53BP1, and suppressing ATM activation and p53 phosphorylation.

Conclusions:

  • DeltaNp73 plays a critical inhibitory role in the DNA damage response pathway.
  • This newly identified function of DeltaNp73 may contribute to chemotherapy resistance in human tumors with high DeltaNp73 expression.

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