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Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate

Yung-Tuen Chiu1, Ji Liu, Kaidun Tang

  • 1Department of Anatomy, The University of Hong Kong, Hong Kong, Special Administrative Region, China.

Plos One
|December 29, 2012
PubMed

Insights

The ATM/ATR DNA damage checkpoint is crucial for genetic stability. Its inactivation promotes prostate cancer by enabling androgen-induced genomic instability and specific gene rearrangements.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The ATM/ATR DNA damage checkpoint is vital for maintaining genetic stability.
  • Some ATM gene variants are linked to increased prostate cancer risk, but direct causal links remain unclear.

Purpose of the Study:

  • To investigate the role of the ATM/ATR DNA damage checkpoint in prostate cancer predisposition.
  • To determine if ATM/ATR inactivation contributes to androgen-induced genomic instability in prostate cells.

Main Methods:

  • Exposure of non-malignant prostate epithelial cells (HPr-1AR) to androgen.
  • Knockdown of ATM gene expression.
  • Analysis of TMPRSS2:ERG rearrangement and DNA damage response pathways (ATM/ATR, H2AX, CHK1/CHK2, p53).

Main Results:

  • Androgen exposure activates ATM/ATR and induces senescence in normal prostate cells.
  • ATM knockdown promotes androgen-induced TMPRSS2:ERG rearrangement.
  • Prostate cancer cells exhibit defective ATM/ATR checkpoint response to androgen, with partial DNA damage response activation.

Conclusions:

  • ATM/ATR inactivation is a critical event in promoting androgen-induced genomic instability.
  • This inactivation facilitates prostate carcinogenesis by enabling specific chromosomal translocations.

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