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A positive role for c-Abl in Atm and Atr activation in DNA damage response

X Wang1, L Zeng, J Wang

  • 1Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.

Cell Death and Differentiation
|August 28, 2010
PubMed

Insights

The non-receptor tyrosine kinase c-Abl is crucial for DNA damage response, acting upstream of Atm and Atr activation. This kinase facilitates DNA repair and cell survival signaling pathways.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA damage activates Atm and Atr signaling for cell cycle control, apoptosis, and repair.
  • The precise activation mechanisms of Atm and Atr remain incompletely understood.
  • c-Abl, a downstream target of Atm, traditionally relays apoptotic signals to p53 and p73.

Purpose of the Study:

  • To investigate the role of c-Abl in DNA damage response pathways.
  • To determine if c-Abl acts upstream of Atm and Atr activation.
  • To elucidate c-Abl's function in genotoxic stress response.

Main Methods:

  • Analysis of c-Abl deficient cells under genotoxic stress.
  • Assessing activation of signaling proteins like Chk1, Chk2, and p53.
  • Investigating c-Abl's interaction with Atm and Atr on chromatin.
  • Mapping phosphorylation sites of Atr by c-Abl.

Main Results:

  • c-Abl deficiency impairs multiple DNA damage responses, including Chk1/Chk2 and p53 activation, DNA repair, and apoptosis.
  • c-Abl is essential for the proper activation of both Atm and Atr.
  • c-Abl binds chromatin and enhances interaction with Atm and Atr upon DNA damage.
  • c-Abl phosphorylates Atr at Y291 and Y310, promoting Atr activation.

Conclusions:

  • c-Abl plays a critical role upstream of Atm and Atr activation in response to genotoxic stress.
  • c-Abl's function extends beyond relaying signals to p53/p73, actively participating in initiating DNA damage cascades.
  • Atm-mediated c-Abl activation contributes to the coordinated activation of Atm and Atr, ensuring robust cellular responses to DNA damage.

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