title: A Role for the Twins Protein Phosphatase (PP2A-B55) in the Maintenance ofDrosophilaGenome Integrity.
abstract: The protein phosphatase 2A (PP2A) is a conserved heterotrimeric enzyme that regulates several cellular processes including the DNA damage response and mitosis. Consistent with these functions, PP2A is mutated in many types of cancer and acts as a tumor suppressor. In mammalian cells, PP2A inhibition results in DNA double strand breaks (DSBs) and chromosome aberrations (CABs). However, the mechanisms through which PP2A prevents DNA damage are still unclear. Here, we focus on the role of theDrosophila twins(tws) gene in the maintenance of chromosome integrity;twsencodes the B regulatory subunit (B/B55) of PP2A. Mutations intwscause high frequencies of CABs (0.5 CABs/cell) inDrosophilalarval brain cells and lead to an abnormal persistence of γ-H2Av repair foci. However, mutations that disrupt the PP4 phosphatase activity impair foci dissolution but do not cause CABs, suggesting that a delayed foci regression is not clastogenic. We also show that Tws is required for activation of the G2/M DNA damage checkpoint while PP4 is required for checkpoint recovery, a result that points to a conserved function of these phosphatases from flies to humans. Mutations in the ATM-coding genetefuare strictly epistatic totwsmutations for the CAB phenotype, suggesting that failure to dephosphorylate an ATM substrate(s) impairs DNA DSBs repair. In addition, mutations in theKu70gene, which do not cause CABs, completely suppress CAB formation intws Ku70double mutants. These results suggest the hypothesis that an improperly phosphorylated Ku70 protein can lead to DNA damage and CABs.
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza, Università di Roma, 00185, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Merigliano
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza, Università di Roma, 00185, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Marzio
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza, Università di Roma, 00185, Italy.
authors.forename: Fioranna
authors.initials: F
authors.lastname: Renda
authors.affiliation: Istituto di Biologia e Patologia Molecolari del Consiglio Nazionale delle Ricerche, Sapienza, Università di Roma, 00185, Italy.
authors.forename: Maria Patrizia
authors.initials: MP
authors.lastname: Somma
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza, Università di Roma, 00185, Italy maurizio.gatti@uniroma1.it fiammetta.verni@uniroma1.it.|Istituto di Biologia e Patologia Molecolari del Consiglio Nazionale delle Ricerche, Sapienza, Università di Roma, 00185, Italy.
authors.forename: Maurizio
authors.identifier: 0000-0003-3777-300X
authors.initials: M
authors.lastname: Gatti
authors.affiliation: Dipartimento di Biologia e Biotecnologie "C. Darwin," Sapienza, Università di Roma, 00185, Italy maurizio.gatti@uniroma1.it fiammetta.verni@uniroma1.it.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Vernì
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D059565:G2 Phase Cell Cycle Checkpoints; D042822:Genomic Instability; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; C514947:Tefu protein, Drosophila; D010749:Phosphoprotein Phosphatases; C079898:tws protein, Drosophila
keywords: ATM; Drosophila; Ku70; PP2A-B55; Tws; chromosome aberrations