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

First Author  Mamouni K Year  2014
Journal  Mol Cell Biol Volume  34
Issue  16 Pages  3144-55
PubMed ID  24912678 Mgi Jnum  J:224276
Mgi Id  MGI:5661806 Doi  10.1128/MCB.01525-13
Citation  Mamouni K, et al. (2014) RhoB promotes gammaH2AX dephosphorylation and DNA double-strand break repair. Mol Cell Biol 34(16):3144-55
abstractText  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 gammaH2AX 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 gammaH2AX and other DNA damage and repair proteins. Thus, we propose that DSBs activate a Chk2-HuR-RhoB pathway that promotes PP2A-mediated dephosphorylation of gammaH2AX and DSB repair. Finally, we show that RhoB-deficient cells accumulate endogenous gammaH2AX and chromosomal abnormalities, suggesting that RhoB loss increases DSB-mediated genomic instability and tumor progression.
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