title: Novel functions of the phosphatase SHP2 in the DNA replication and damage checkpoints.
abstract: Replication stress- and DNA damage-induced cell cycle checkpoints are critical for maintaining genome stability. To identify protein phosphatases involved in the activation and maintenance of the checkpoints, we have carried out RNA interference-based screens with a human phosphatome shRNA library. Several phosphatases, including SHP2 (also called PTPN11) were found to be required for cell survival upon hydroxyurea-induced replicative stress in HeLa cells. More detailed studies revealed that SHP2 was also important for the maintenance of the checkpoint after DNA damage induced by cisplatin or ionizing radiation in HeLa cells. Furthermore, SHP2 was activated after replicative stress and DNA damage. Although depletion of SHP2 resulted in a delay in cyclin E accumulation and an extension of G(1) phase, these cell cycle impairments were not responsible for the increase in apoptosis after DNA damage. Depletion of SHP2 impaired CHK1 activation, checkpoint-mediated cell cycle arrest, and DNA repair. These effects could be rescued with a shRNA-resistant SHP2. These results underscore the importance of protein phosphatases in checkpoint control and revealed a novel link between SHP2 and cell cycle checkpoints.
authors.affiliation: Division of Life Science and Center for Cancer Research, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Yiu Huen
authors.initials: YH
authors.lastname: Tsang
authors.forename: Xianxian
authors.initials: X
authors.lastname: Han
authors.forename: Wing Yu
authors.initials: WY
authors.lastname: Man
authors.forename: Nelson
authors.initials: N
authors.lastname: Lee
authors.forename: Randy Y C
authors.initials: RY
authors.lastname: Poon
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D019927:Cyclin E / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016196:S Phase
chemical_list: D019927:Cyclin E; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D002945:Cisplatin; D006918:Hydroxyurea