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Uncoupling Sae2 Functions in Downregulation of Tel1 and Rad53 Signaling Activities

Chiara Vittoria Colombo1, Luca Menin1, Riccardo Ranieri1

  • 1Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milan, Italy.

Genetics
|December 13, 2018
PubMed

Insights

Sae2 protein regulates DNA double-strand break (DSB) repair by controlling the Mre11-Rad50-Xrs2 (MRX) complex and checkpoint proteins. Sae2

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The Mre11-Rad50-Xrs2 (MRX) complex and Sae2 protein are crucial for initiating DNA double-strand break (DSB) resection and regulating checkpoint responses.
  • Sae2's role in DNA damage resistance and its regulation of MRX, Tel1, and Rad53 checkpoint proteins are not fully understood.
  • The interplay between Sae2's functions in DNA damage response and cell cycle regulation requires further elucidation.

Purpose of the Study:

  • To investigate the distinct functions of Sae2 in DNA double-strand break (DSB) repair and checkpoint activation.
  • To characterize a novel separation-of-function mutant, sae2-ms, to dissect Sae2's roles.
  • To elucidate the mechanisms by which Sae2 mediates DNA damage resistance and regulates resection and checkpoint signaling.

Main Methods:

  • Genetic analysis of a novel sae2-ms mutant in yeast.
  • Assessment of DNA damage sensitivity and checkpoint protein activation (Tel1, Rad53, Rad9).
  • Analysis of Mre11 endonuclease activity and long-range resection at DSBs.

Main Results:

  • The sae2-ms mutant, like SAE2 deletion, upregulates MRX and Tel1 signaling by reducing Mre11 endonuclease activity.
  • Unlike SAE2 deletion, sae2-ms does not confer DNA damage sensitivity or enhanced Rad53 activation, indicating Sae2-mediated Rad53 inhibition is key for resistance.
  • Lack of Sae2, but not sae2-ms, impairs long-range resection and increases Rad9 accumulation and Rad53-Rad9 interaction independently of Mre11 nuclease activity.

Conclusions:

  • Sae2 plays distinct roles in limiting MRX-Tel1 and Rad9 abundance at DSBs.
  • Control over Rad9 association is critical for Sae2-mediated DNA damage resistance, long-range resection, and checkpoint activation.
  • A model is proposed where Sae2's functions are separable, with Rad9 regulation being paramount for DNA repair and checkpoint control.
Keywords:
MRXRad53Rad9Sae2Tel1

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