TAILIEUCHUNG - Báo cáo khoa học: Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage

Cisplatin (cis-diamminedichloroplatinum) and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cerevisiae with separate deletions of the genes encoding the trimeric protein serine⁄threonine phosphatase (Pph)3p–platinum sensitivity (Psy)4p–Psy2p complex, are more sensitive than the isogenic wild-type (WT) strain to cisplatin. | ỊFEBS Journal Characterization of the role of a trimeric protein phosphatase complex in recovery from cisplatin-induced versus noncrosslinking DNA damage Cristina Vazquez-Martin John Rouse and Patricia T. W. Cohen MedicalResearch CouncilProtein Phosphorylation Unit College of Life Sciences University of Dundee UK Keywords cisplatin histone 2AX methylmethanesulfonate PPH3 protein phosphatase 4 Correspondence P. T. W. Cohen MRC Protein Phosphorylation Unit College of Life Sciences Sir James Black Centre University of Dundee Dow Street Dundee DD1 5EH UK Fax 44 1382 223778 Tel 44 1382 384240 E-mail Received 29 April2008 revised 11 May 2008 accepted 23 June 2008 doi Cisplatin cis-diamminedichloroplatinum and related chemotherapeutic DNA-crosslinking agents are widely used to treat human cancers. Saccha-romyces cerevisiae with separate deletions of the genes encoding the trimeric protein serine threonine phosphatase Pph 3p-platinum sensitivity Psy 4p-Psy2p complex are more sensitive than the isogenic wild-type WT strain to cisplatin. We show here that cisplatin causes an enhanced intra-S-phase cell cycle delay in these three deletion mutants. The C-termi-nal tail of histone 2AX H2AX is hyperphosphorylated in the same mutants and Pph3p is found to interact with phosphorylated H2AX yH2AX . After cisplatin treatment is terminated pph3D psy4D and psy2D mutants are delayed as compared with the WT strain in the dephosphorylation of Rad53p. In contrast only pph3D and psy2D cells are more sensitive than WT cells to methylmethanesulfonate a noncrosslinking DNA-alkylat-ing agent that is known to cause a Rad53p-dependent intra-S-phase cell cycle delay. Dephosphorylation of Rad53p and the recovery of chromosome replication are delayed in the same mutants but not in psy4D cells. By comparison with their mammalian orthologues the regulatory subunit Psy4p is likely to inhibit Pph3p catalytic activity. The presence of a weak but

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