title: RhoB promotes γH2AX dephosphorylation and DNA double-strand break repair.
abstract: Unlike other Rho GTPases, RhoB is rapidly induced by DNA damage, and its expression level decreases during cancer progression. Because inefficient repair of DNA double-strand breaks (DSBs) can lead to cancer, we investigated whether camptothecin, an anticancer drug that produces DSBs, induces RhoB expression and examined its role in the camptothecin-induced DNA damage response. We show that in camptothecin-treated cells, DSBs induce RhoB expression by a mechanism that depends notably on Chk2 and its substrate HuR, which binds to RhoB mRNA and protects it against degradation. RhoB-deficient cells fail to dephosphorylate γH2AX following camptothecin removal and show reduced efficiency of DSB repair by homologous recombination. These cells also show decreased activity of protein phosphatase 2A (PP2A), a phosphatase for γH2AX and other DNA damage and repair proteins. Thus, we propose that DSBs activate a Chk2-HuR-RhoB pathway that promotes PP2A-mediated dephosphorylation of γH2AX and DSB repair. Finally, we show that RhoB-deficient cells accumulate endogenous γH2AX and chromosomal abnormalities, suggesting that RhoB loss increases DSB-mediated genomic instability and tumor progression.
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France.
authors.forename: Kenza
authors.initials: K
authors.lastname: Mamouni
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France.
authors.forename: Agnese
authors.initials: A
authors.lastname: Cristini
authors.affiliation: CNRS UMR8200, Institut de Cancérologie Gustave Roussy, Université Paris XI, Villejuif, France.
authors.forename: Josée
authors.initials: J
authors.lastname: Guirouilh-Barbat
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monferran
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lemarié
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Faye
authors.affiliation: CNRS UMR8200, Institut de Cancérologie Gustave Roussy, Université Paris XI, Villejuif, France.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France favre.gilles@claudiusregaud.fr olivier.sordet@inserm.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.affiliation: Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France favre.gilles@claudiusregaud.fr olivier.sordet@inserm.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sordet
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D051959:ELAV Proteins / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D020743:rhoB GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051959:ELAV Proteins; D006657:Histones; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D059004:Topoisomerase I Inhibitors; C475961:gamma-H2AX protein, mouse; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D054648:Protein Phosphatase 2; D020743:rhoB GTP-Binding Protein; D002166:Camptothecin