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Structural insights into the critical DNA damage sensors DNA-PKcs, ATM and ATR

Domagoj Baretic1, Taiana Maia de Oliveira2, Martina Niess3

  • 1Laboratory of Molecular Biology - MRC, Cambridge, UK.

Progress in Biophysics and Molecular Biology
|July 1, 2019
PubMed

Insights

Recent Cryo-EM advances reveal the structures of key DNA damage response proteins: ATM, ATR, and DNA-PKcs. Our study highlights novel conformations and arrangements, offering new insights into cancer cell survival and radio/chemotherapy response.

Area of Science:

  • Molecular biology
  • Structural biology
  • Cancer research

Background:

  • ATM, ATR, and DNA-PKcs are crucial for DNA damage response (DDR).
  • These proteins are implicated in cancer development and survival post-treatment.
  • Their structures were previously unknown, hindering mechanistic understanding.

Purpose of the Study:

  • To review and present the structures of ATM, ATR, and DNA-PKcs and their complexes.
  • To detail novel structural observations from cryo-electron microscopy (cryo-EM) studies.
  • To enhance understanding of DDR protein function in cancer.

Main Methods:

  • Comprehensive review of existing structural data.
  • Cryo-electron microscopy (cryo-EM) for high-resolution structure determination.
  • Analysis of protein structures and complex formations.

Main Results:

  • The resolution revolution in cryo-EM has enabled visualization of ATM, ATR, and DNA-PKcs structures.
  • Novel conformations of ATR have been identified.
  • New dimeric arrangements of DNA-PKcs have been observed.

Conclusions:

  • Structural insights into ATM, ATR, and DNA-PKcs are now available.
  • These findings provide a foundation for understanding their roles in cancer.
  • Further research into these structures may reveal therapeutic targets.

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