title: A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint.
abstract: DNA replication is executed only when cells have sufficient metabolic resources and undamaged DNA. Nutrient limitation and DNA damage cause a metabolic checkpoint and DNA damage checkpoint, respectively. Although SIRT1 activity is regulated by metabolic stress and DNA damage, its function in these stress-mediated checkpoints remains elusive. Here we report that the SIRT1-TopBP1 axis functions as a switch for both checkpoints. With glucose deprivation, SIRT1 is activated and deacetylates TopBP1, resulting in TopBP1-Treslin disassociation and DNA replication inhibition. Conversely, SIRT1 activity is inhibited under genotoxic stress, resulting in increased TopBP1 acetylation that is important for the TopBP1-Rad9 interaction and activation of the ATR-Chk1 pathway. Mechanistically, we showed that acetylation of TopBP1 changes the conformation of TopBP1, thereby facilitating its interaction with distinct partners in DNA replication and checkpoint activation. Taken together, our studies identify the SIRT1-TopBP1 axis as a key signaling mode in the regulation of the metabolic checkpoint and the DNA damage checkpoint.
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wenchuan
authors.initials: W
authors.lastname: Leng
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Evans
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: yuanjian229@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lou.zhenkun@mayo.edu.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000107:Acetylation; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C069930:rad9 protein; D056564:Sirtuin 1