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Mec1 is Activated at the Onset of Normal S Phase by Low dNTP Pools Impeding DNA Replication

48 Pages Posted: 13 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Romain Forey

Romain Forey

University of Montpellier - Institute of Human Genetics

Ana Poveda

University of Montpellier - Institute of Human Genetics

sushma sharma

University of Umea - Department of Medical Biochemistry and Biophysics

Ismael Padioleau

University of Montpellier - Institute of Human Genetics

Claire Renard

University of Montpellier - Institute of Human Genetics

Robin Lambert

University of Montpellier - Institute of Human Genetics

Magdalena Skrzypczak

University of Warsaw - Laboratory of Bioinformatics and Systems Biology

Krzysztof Ginalski

University of Warsaw - Laboratory of Bioinformatics and Systems Biology

Armelle Lengronne

University of Montpellier - Institute of Human Genetics

Andrei Chabes

University of Umea - Department of Medical Biochemistry and Biophysics

Benjamin Pardo

University of Montpellier - Institute of Human Genetics

Philippe Pasero

University of Montpellier - Institute of Human Genetics

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Abstract

The Mec1 and Rad53 kinases play a central role during acute replication stress in budding yeast. They are also essential for viability in normal growth conditions, but the signal that activates the Mec1-Rad53 pathway in the absence of exogenous insults is currently unknown. Here, we show that this pathway is active at the onset of normal S phase because dNTP levels present in G1 phase are not sufficient to support processive DNA synthesis and impede DNA replication. This activation can be suppressed experimentally by increasing dNTP levels in G1 phase. Moreover, we show that unchallenged cells entering S phase in the absence of Rad53 undergo irreversible fork collapse and mitotic catastrophe. Together, these data indicate that cells use dNTP shortage to detect the onset of DNA replication and activate the Mec1-Rad53 pathway, which in turn maintains functional forks and triggers dNTP synthesis, allowing the completion of DNA replication.

Keywords: DNA replication, S-phase checkpoint, dNTP synthesis, cell cycle, budding yeast

Suggested Citation

Forey, Romain and Poveda, Ana and sharma, sushma and Padioleau, Ismael and Renard, Claire and Lambert, Robin and Skrzypczak, Magdalena and Ginalski, Krzysztof and Lengronne, Armelle and Chabes, Andrei and Pardo, Benjamin and Pasero, Philippe, Mec1 is Activated at the Onset of Normal S Phase by Low dNTP Pools Impeding DNA Replication (September 10, 2019). MOLECULAR-CELL-D-19-01550. Available at SSRN: https://ssrn.com/abstract=3451454 or http://dx.doi.org/10.2139/ssrn.3451454
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Romain Forey

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Ana Poveda

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Sushma Sharma

University of Umea - Department of Medical Biochemistry and Biophysics ( email )

Sweden

Ismael Padioleau

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Claire Renard

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Robin Lambert

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Magdalena Skrzypczak

University of Warsaw - Laboratory of Bioinformatics and Systems Biology

Poland

Krzysztof Ginalski

University of Warsaw - Laboratory of Bioinformatics and Systems Biology

Poland

Armelle Lengronne

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Andrei Chabes

University of Umea - Department of Medical Biochemistry and Biophysics

Sweden

Benjamin Pardo

University of Montpellier - Institute of Human Genetics

163 rue Auguste Broussonnet
France

Philippe Pasero (Contact Author)

University of Montpellier - Institute of Human Genetics ( email )

163 rue Auguste Broussonnet
France

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