ATR and ATM regulate the timing of DNA replication origin firing

Nature Cell Biology
David ShechterJ Gautier

Abstract

Timing of DNA replication initiation is dependent on S-phase-promoting kinase (SPK) activity at discrete origins and the simultaneous function of many replicons. DNA damage prevents origin firing through the ATM- and ATR-dependent inhibition of Cdk2 and Cdc7 SPKs. Here, we establish that modulation of ATM- and ATR-signalling pathways controls origin firing in the absence of DNA damage. Inhibition of ATM and ATR with caffeine or specific neutralizing antibodies, or upregulation of Cdk2 or Cdc7, promoted rapid and synchronous origin firing; conversely, inhibition of Cdc25A slowed DNA replication. Cdk2 was in equilibrium between active and inactive states, and the concentration of replication protein A (RPA)-bound single-stranded DNA (ssDNA) correlated with Chk1 activation and inhibition of origin firing. Furthermore, ATM was transiently activated during ongoing replication. We propose that ATR and ATM regulate SPK activity through a feedback mechanism originating at active replicons. Our observations establish that ATM- and ATR-signalling pathways operate during an unperturbed cell cycle to regulate initiation and progression of DNA synthesis, and are therefore poised to halt replication in the presence of DNA damage.

References

Aug 1, 1995·The Journal of Cell Biology·P K JacksonM W Kirschner
Feb 14, 1997·Science·J Walter, J W Newport
Jul 14, 1998·Molecular Cell·J WalterJ Newport
Jul 25, 2000·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·S MimuraH Takisawa
Jul 25, 2000·Journal of Molecular Biology·J HerrickA Bensimon
Aug 31, 2000·Annual Review of Biochemistry·T J Kelly, G W Brown
Mar 30, 2001·The Journal of Biological Chemistry·K Marheineke, O Hyrien
Sep 7, 2001·Genes & Development·R T Abraham
Oct 26, 2002·Proceedings of the National Academy of Sciences of the United States of America·Hui ZhaoHelen Piwnica-Worms
Nov 26, 2002·Molecular and Cellular Biology·Timothy P HeffernanWilliam K Kaufmann
Jan 23, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Olivier HyrienArach Goldar
Jun 7, 2003·Science·Lee Zou, Stephen J Elledge
May 13, 2004·PLoS Biology·Vincenzo CostanzoJean Gautier

❮ Previous
Next ❯

Citations

Dec 14, 2011·Journal of Molecular Modeling·Claudio CarraFrancis A Cucinotta
Dec 17, 2009·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Makoto NakanishiMidori Shimada
Mar 6, 2010·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Olivier Hyrien, Arach Goldar
Dec 30, 2009·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Sandie TuduriPhilippe Pasero
Jul 15, 2006·Journal of Molecular Histology·Midori Shimada, Makoto Nakanishi
Jun 1, 2005·Mutation Research·Mats Ljungman
Nov 19, 2004·Nature·Michael B Kastan, Jiri Bartek
Jul 3, 2004·Nature Cell Biology·Daniel Fisher, Marcel Méchali
Dec 2, 2006·Nature Cell Biology·Nicholas Rhind
Apr 13, 2010·Nature Cell Biology·Alessia BalestriniVincenzo Costanzo
Jun 13, 2006·Nature Chemical Biology·Jaejoon WonTae Kook Kim
May 16, 2013·Nature Communications·Catherine Bonne-AndreaOlivier Coux
Jun 5, 2007·Nature Protocols·David ShechterSandra B Hake
May 23, 2009·Nature Reviews. Cancer·Steffi HeroldMartin Eilers
Jul 3, 2013·Nature Reviews. Drug Discovery·Everett J ModingDavid G Kirsch
Oct 2, 2004·Nature Reviews. Molecular Cell Biology·Jiri BartekJiri Lukas
Dec 2, 2004·Nature Reviews. Molecular Cell Biology·Kristijan RamadanUlrich Hübscher
Jul 3, 2008·Nature Reviews. Molecular Cell Biology·Karlene A Cimprich, David Cortez
Sep 24, 2010·Nature Reviews. Molecular Cell Biology·Marcel Méchali
Feb 18, 2009·Proceedings of the National Academy of Sciences of the United States of America·Yuko KatsunoMakoto Nakanishi
Jan 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·David ShechterC David Allis
Sep 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Eva PetermannThomas Helleday
Oct 2, 2013·Proceedings of the National Academy of Sciences of the United States of America·Frederik KöpperMatthias Dobbelstein
Jul 28, 2009·The Journal of Biological Chemistry·Alexandra SobeckMaureen E Hoatlin
Feb 6, 2007·The Journal of Biological Chemistry·Timothy P HeffernanWilliam K Kaufmann
Oct 1, 2013·Cellular Reprogramming·Gloryn Chia, Dieter Egli
Sep 29, 2006·Molecular Biology of the Cell·Ronald LebofskyAaron Bensimon
Feb 24, 2006·Carcinogenesis·Paul R AndreassenAlan D D'Andrea
Aug 29, 2006·Nucleic Acids Research·Ellen FanningAndrew R Nager
Feb 25, 2009·Nucleic Acids Research·Liliana Krasinska, Daniel Fisher
Nov 13, 2009·Nucleic Acids Research·Isabel Kurth, Jean Gautier
Dec 22, 2011·Nucleic Acids Research·Bénédicte RecolinDomenico Maiorano

❮ Previous
Next ❯

Related Concepts

Related Feeds

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Ataxia telangiectasia

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.