Abstract
RHO GTPases regulate essential functions such as the organization of the actin cytoskeleton. The classic members cycle between an active GTP-bound and an inactive GDP-bound conformation whereas atypical members are predominantly GTP-bound. Besides their well-established role, the classic RHO GTPases RHOB and RAC1, are rapidly induced and/or activated by genotoxic stress and contribute to the DNA damage response. Here we used camptothecin, a selective topoisomerase I (TOP1) inhibitor that stabilizes TOP1 cleavage complexes (TOP1cc), to search for other potential early DNA damage-inducible RHO GTPase genes. We identified that an atypical RHO GTPase, RND1, is rapidly induced by camptothecin. RND1 induction is closely associated with the presence of TOP1cc induced by camptothecin or by DNA lesions that elevate TOP1cc levels such as UV and hydrogen peroxide. We further demonstrated that camptothecin increases RND1 gene transcription and mRNA stability. Camptothecin also increases poly(ADP-ribose) polymerase 1 (PARP-1) activity, whose inhibition reduces RND1 transcription. In addition, overexpression of RND1 increases PARP-1, suggesting a cross-talk between PARP-1 and RND1. Finally, RND1 protects cells against camptothecin-induced apoptosis, and hence favors cellular resistance to camptothecin. Together, these findings highlight RND1 as an atypical RHO GTPase early induced by TOP1cc, and show that the TOP1cc-PARP-1-RND1 pathway protects cells against apoptosis induced by camptothecin.
Highlights
Introduction The RHO GTPase family comprises20 members in human, which can be divided into classic and atypical members[1]
RHO GTPase mRNA expression by reverse transcription followed by qPCR (RT-qPCR) (Fig. 1a)
The increase of RND1 protein levels promotes an increase of poly(ADP-ribose) polymerase 1 (PARP-1) protein levels, suggesting a positive feedback loop between PARP1 and RND1 in response to CPT
Summary
Introduction The RHO GTPase family comprises20 members in human, which can be divided into classic and atypical members[1]. Classic RHO GTPases, such as RHOB and RAC1, cycle between an active GTP-bound and an inactive GDP-bound conformation. Atypical RHO GTPases, such as RND1, are unable to hydrolyze GTP and are Besides their canonical roles, the RHO GTPases RAC1 and RHOB have been implicated in the early response to DNA damage. Unlike RAC1 that is primarily activated in response to DNA damage without change in expression[7,8], RHOB is both induced and activated[9,10,11,12]. Increased expression of RHOB promotes DNA repair and confers cell resistance to genotoxic stress[9]. At present, it is not known whether, besides RHOB, other RHO GTPases are early DNA damage-inducible genes, at the expression level
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