RhoB Promotes γH2AX Dephosphorylation and DNA Double-Strand Break Repair

Abstract

c 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 ␥H2AX 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 ␥H2AX and other DNA damage and repair proteins. Thus, we propose that DSBs activate a Chk2-HuR-RhoB pathway that promotes PP2A-mediated dephosphorylation of ␥H2AX and DSB repair. Finally, we show that RhoB-deficient cells accumulate endogenous ␥H2AX and chromosomal abnormalities, suggesting that RhoB loss increases DSB-mediated genomic instability and tumor progression.

Localisation of Nup153 and SENP1 to nuclear pore complexes is required for 53BP1-mediated DNA double-strand break repair

“…In contrast to a previous study (Lemaitre et al, 2012), we noticed no shift from NHEJ to HR in Nup153-depleted cells. This discrepancy might arise from the different cell lines that were used; U2OS cells in our study and the human fibroblast line GC92 in the previous study (Lemaitre et al, 2012;Mamouni et al, 2014;Rass et al, 2009). Our data are, however, consistent with the fact that 53BP1 promotes the fidelity of homology-directed DNA repair (Ochs et al, 2016).…”

RhoGTPases – A novel link between cytoskeleton organization and cisplatin resistance

“…Moreover, RhoB is an early DNA damage inducible gene, and its expression is induced by various genotoxic agents, including UV and cisplatin (Canguilhem et al, 2005). A recent publication suggests that loss of RhoB could promote oncogenesis as a result of increased double-strand break-mediated genomic instability (Mamouni et al, 2014).…”

Inhibitory Effect of α-Pinene on SGC-7901 Cell Proliferation and the Mechanism of ATM Kinase Signaling Pathway

“…Then, p-ATM phosphorylate and active its substrate H2AX become rH2AX. rH2AX is the earliest phosphorylation product and also is the characterictic product in DNA damage response [15] [16]. CHK2 is the main protein downstream of ATM, it would be inactive while it phosphorylated to p-CHK2 by ATM and consequently induces cell cycle arrest [17].…”