title: A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication.
abstract: A key function of the cellular DNA damage response is to facilitate the bypass of replication fork-stalling DNA lesions. Template switch reactions allow such a bypass and involve the formation of DNA joint molecules (JMs) between sister chromatids. These JMs need to be resolved before cell division; however, the regulation of this process is only poorly understood. Here, we identify a regulatory mechanism in yeast that critically controls JM resolution by the Mus81-Mms4 endonuclease. Central to this regulation is a conserved complex comprising the scaffold proteins Dpb11 and Slx4 that is under stringent control. Cell cycle-dependent phosphorylation of Slx4 by Cdk1 promotes the Dpb11-Slx4 interaction, while in mitosis, phosphorylation of Mms4 by Polo-like kinase Cdc5 promotes the additional association of Mus81-Mms4 with the complex, thereby promoting JM resolution. Finally, the DNA damage checkpoint counteracts Mus81-Mms4 binding to the Dpb11-Slx4 complex. Thus, Dpb11-Slx4 integrates several cellular inputs and participates in the temporal program for activation of the JM-resolving nuclease Mus81.
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Dalia
authors.initials: D
authors.lastname: Gritenaite
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Lissa N
authors.initials: LN
authors.lastname: Princz
authors.affiliation: Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy;
authors.forename: Barnabas
authors.initials: B
authors.lastname: Szakal
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Susanne C S
authors.initials: SC
authors.lastname: Bantele
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Lina
authors.initials: L
authors.lastname: Wendeler
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Sandra
authors.initials: S
authors.lastname: Schilbach
authors.affiliation: Computational Biology, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Bianca H
authors.initials: BH
authors.lastname: Habermann
authors.affiliation: Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, 8093 Zürich, Switzerland;
authors.forename: Joao
authors.initials: J
authors.lastname: Matos
authors.affiliation: Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Lisby
authors.affiliation: Fondazione IFOM, Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy;
authors.forename: Dana
authors.initials: D
authors.lastname: Branzei
authors.affiliation: DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;
authors.forename: Boris
authors.initials: B
authors.lastname: Pfander
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C097185:DPB11 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D004706:Endodeoxyribonucleases; C505436:SLX4 protein, S cerevisiae
keywords: DNA damage response; cell cycle; homologous recombination; joint molecule resolution; post-replicative repair