title: Restriction of replication fork regression activities by a conserved SMC complex.
abstract: Conserved, multitasking DNA helicases mediate diverse DNA transactions and are relevant for human disease pathogenesis. These helicases and their regulation help maintain genome stability during DNA replication and repair. We show that the structural maintenance of chromosome complex Smc5-Smc6 restrains the replication fork regression activity of Mph1 helicase, but not its D loop disruptive activity. This regulatory mechanism enables flexibility in replication fork repair without interfering with DNA break repair. In vitro studies find that Smc5-Smc6 binds to a Mph1 region required for efficient fork regression, preventing assembly of Mph1 oligomers at the junction of DNA forks. In vivo impairment of this regulatory mechanism compensates for the inactivation of another fork regression helicase and increases reliance on joint DNA structure removal or avoidance. Our findings provide molecular insights into replication fork repair regulation and uncover a role of Smc5-Smc6 in directing Mph1 activity toward a specific biochemical outcome.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xue
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Programs in Biochemistry, Cell, and Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Koyi
authors.initials: K
authors.lastname: Choi
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Programs in Biochemistry, Cell, and Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Bonner
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Youngho
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Departments of Radiation Oncology and Genetics, Cancer Genomics Center, Erasmus University Medical Center, 3000CA Rotterdam, the Netherlands.
authors.forename: Humberto
authors.initials: H
authors.lastname: Sanchez
authors.affiliation: Departments of Radiation Oncology and Genetics, Cancer Genomics Center, Erasmus University Medical Center, 3000CA Rotterdam, the Netherlands.
authors.forename: Claire
authors.initials: C
authors.lastname: Wyman
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hengyao
authors.initials: H
authors.lastname: Niu
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Programs in Biochemistry, Cell, and Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA. Electronic address: zhaox1@mskcc.org.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: patrick.sung@yale.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sung
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism; D004261:DNA Replication; D004271:DNA, Fungal / Q000096:biosynthesis; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; C486627:SMC5 protein, S cerevisiae; C486631:SMC6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C491240:MPH1 protein, S cerevisiae; D053487:DEAD-box RNA Helicases