Abstract
Accumulating evidence has suggested a role of the small GTPase Ras homolog gene family member A (RhoA) in DNA damage response (DDR) in addition to its traditional function of regulating cell morphology. In DDR, 2 key components of DNA repair, ataxia telangiectasia-mutated (ATM) and flap structure-specific endonuclease 1 (FEN1), along with intracellular reactive oxygen species (ROS) have been shown to regulate RhoA activation. In addition, Rho-specific guanine exchange factors (GEFs), neuroepithelial transforming gene 1 (Net1) and epithelial cell transforming sequence 2 (Ect2), have specific functions in DDR, and they also participate in Ras-related C3 botulinum toxin substrate 1 (Rac1)/RhoA interaction, a process which is largely unappreciated yet possibly of significance in DDR. Downstream of RhoA, current evidence has highlighted its role in mediating cell cycle arrest, which is an important step in DNA repair. Unraveling the mechanism by which RhoA modulates DDR may provide more insight into DDR itself and may aid in the future development of cancer therapies.
Highlights
In research on signal transduction molecules, GTP-binding Rho proteins were identified as Ras homologs, and their biological functions were first scrutinized by experiments where Rho inhibition was induced by C3 exoenzyme and microinjection of Ras homolog gene family member A (RhoA) mutants
We focus on the following 4 aspects of this topic: (1) how DNA damage induces RhoA activation; (2) Rho-specific guanine exchange factors (GEFs) neuroepithelial transforming gene 1 (Net1) and epithelial cell transforming sequence 2 (Ect2), and their roles in DNA damage response (DDR); (3) the possible related C3 botulinum toxin substrate 1 (Rac1)/RhoA
In DNA double-strand break (DSB) repair, the lesion is sensed by the Mre-Rad50-Nbs1 (MRN) complex, which subsequently activates ataxia telangiectasia-mutated (ATM) kinase, which in turn initiates a flurry of enzymatic events including the checkpoint kinase 2 (CHK2)-mediated checkpoint
Summary
In research on signal transduction molecules, GTP-binding Rho proteins were identified as Ras homologs, and their biological functions were first scrutinized by experiments where Rho inhibition was induced by C3 exoenzyme and microinjection of Ras homolog gene family member A (RhoA) mutants These functions mainly include stress fiber formation, focal adhesion formation, cytokinesis, and serum response factor (SRF)-dependent transcription. There are 3 steps included in this process: cell cycle arrest, DNA repair, and apoptosis if the damage is beyond repair [20] In addition to such a plethora of research discussing the role of RhoA in cell morphology and motility regulation, there has been a rapid accumulation of data concerning a role of RhoA in DDR (2) Rho-specific GEFs Net and Ect, and their roles in DDR; (3) the possible Rac1/RhoA interactions in DDR; and (4) RhoA-mediated cell cycle arrest and cell survival signaling
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