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Mol Cell Biol. 2014 Aug;34(16):3144-55. doi: 10.1128/MCB.01525-13. Epub 2014 Jun 9.

RhoB promotes γH2AX dephosphorylation and DNA double-strand break repair.

Author information

1
Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France Université de Toulouse, Toulouse, France.
2
CNRS UMR8200, Institut de Cancérologie Gustave Roussy, Université Paris XI, Villejuif, France.
3
Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France.
4
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.
5
Cancer Research Center of Toulouse, INSERM UMR1037, Institut Claudius Regaud, Toulouse, France favre.gilles@claudiusregaud.fr olivier.sordet@inserm.fr.

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.

PMID:
24912678
PMCID:
PMC4135599
DOI:
10.1128/MCB.01525-13
[Indexed for MEDLINE]
Free PMC Article

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