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Phosphoproteomics reveals distinct modes of Mec1/ATR signaling during DNA replication

Francisco Meirelles Bastos de Oliveira1, Dongsung Kim1, José Renato Cussiol1

  • 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.

Molecular Cell
|March 11, 2015
PubMed

Insights

Mec1/ATR kinases are active during normal DNA replication, not just stress. This previously unknown "replication-correlated" activity requires specific factors and differs from their checkpoint role.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Mec1/Tel1 kinases (ATR/ATM) are crucial for DNA replication stress response.
  • Previous studies focused on limited substrates, hindering a full understanding of their in vivo roles.

Purpose of the Study:

  • To systematically and quantitatively monitor Mec1/Tel1 signaling using an unbiased genetic-phosphoproteomic approach.
  • To investigate the distinct roles of Mec1/ATR during normal replication versus replication stress.

Main Methods:

  • Employed a combined genetic-phosphoproteomic strategy for quantitative analysis of Mec1/Tel1 signaling.
  • Utilized a systematic and unbiased approach to identify Mec1/Tel1 activity patterns.

Main Results:

  • Mec1 kinase exhibits significant activity during normal DNA replication, comparable to or exceeding levels during replication stress.
  • This "replication-correlated" Mec1 activity depends on the 9-1-1 clamp and Dna2.
  • Mec1's role in normal replication is distinct from its activation of Rad53.

Conclusions:

  • Mec1/ATR kinases have essential functions during ongoing DNA synthesis, separate from their canonical roles in replication stress response.
  • Unbiased phosphoproteomics reveals novel, non-canonical functions of Mec1/ATR in DNA replication.

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