title: Assembly of Slx4 signaling complexes behind DNA replication forks.
abstract: Obstructions to replication fork progression, referred to collectively as DNA replication stress, challenge genome stability. In Saccharomyces cerevisiae, cells lacking RTT107 or SLX4 show genome instability and sensitivity to DNA replication stress and are defective in the completion of DNA replication during recovery from replication stress. We demonstrate that Slx4 is recruited to chromatin behind stressed replication forks, in a region that is spatially distinct from that occupied by the replication machinery. Slx4 complex formation is nucleated by Mec1 phosphorylation of histone H2A, which is recognized by the constitutive Slx4 binding partner Rtt107. Slx4 is essential for recruiting the Mec1 activator Dpb11 behind stressed replication forks, and Slx4 complexes are important for full activity of Mec1. We propose that Slx4 complexes promote robust checkpoint signaling by Mec1 by stably recruiting Dpb11 within a discrete domain behind the replication fork, during DNA replication stress.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Attila
authors.initials: A
authors.lastname: Balint
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: TaeHyung
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Department of Molecular Biology and Genetics and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Jose Renato
authors.initials: JR
authors.lastname: Cussiol
authors.affiliation: Department of Molecular Biology and Genetics and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Bastos de Oliveira
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Askar
authors.initials: A
authors.lastname: Yimit
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Jiongwen
authors.initials: J
authors.lastname: Ou
authors.affiliation: Institute of Molecular and Cellular Biosciences, Research Center for Epigenetic Disease, University of Tokyo, Tokyo, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Nakato
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Alexey
authors.initials: A
authors.lastname: Gurevich
authors.affiliation: Institute of Molecular and Cellular Biosciences, Research Center for Epigenetic Disease, University of Tokyo, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.affiliation: Department of Molecular Biology and Genetics and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Smolka
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhaolei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre, University of Toronto, Toronto, ON, Canada grant.brown@utoronto.ca.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
mesh_terms: D018797:Cell Cycle Proteins; D004261:DNA Replication; D004271:DNA, Fungal / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; C097185:DPB11 protein, S cerevisiae; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C501265:RTT107 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C505436:SLX4 protein, S cerevisiae
keywords: DNA damage response; Dpb11; Slx4; checkpoint kinase; replication stress