title: MASTL(Greatwall) regulates DNA damage responses by coordinating mitotic entry after checkpoint recovery and APC/C activation.
abstract: The G2 DNA damage checkpoint is one of the most important mechanisms controlling G2-mitosis transition. The kinase Greatwall (MASTL in human) promotes normal G2-mitosis transition by inhibiting PP2A via ARPP19 and ENSA. In this study, we demonstrate that MASTL is critical for maintaining genome integrity after DNA damage. Although MASTL did not affect the activation of DNA damage responses and subsequent repair, it determined the timing of entry into mitosis and the subsequent fate of the recovering cells. Constitutively active MASTL promoted dephosphorylation of CDK1(Tyr15) and accelerated mitotic entry after DNA damage. Conversely, downregulation of MASTL or ARPP19/ENSA delayed mitotic entry. Remarkably, APC/C was activated precociously, resulting in the damaged cells progressing from G2 directly to G1 and skipping mitosis all together. Collectively, these results established that precise control of MASTL is essential to couple DNA damage to mitosis through the rate of mitotic entry and APC/C activation.
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Po Yee
authors.initials: PY
authors.lastname: Wong
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Hoi Tang
authors.initials: HT
authors.lastname: Ma
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Hyun-jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Randy Y C
authors.initials: RY
authors.lastname: Poon
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D064200:Cdh1 Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D064200:Cdh1 Proteins; D008869:Microtubule-Associated Proteins; D064173:Anaphase-Promoting Complex-Cyclosome; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase