Role of Small GTPase RhoA in DNA Damage Response

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.

Keywords: DNA damage response; DNA repair; Ect2; Net1; Rac1; RhoA; cell cycle arrest.

Figure 1

A brief summary of the Ras-related C3 botulinum toxin substrate (Rac1)/RhoA interaction: Rac1 may activate nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NOX), which generates reactive oxygen species (ROS) and then promotes the activity of p190RhoGAP. The GTPase-activating factor (GAP) induces hydrolysis of GTP and inactivates RhoA. Rac1 may also downregulate RhoA through p21-activated kinase 1 (PAK1), which inhibits the guanine exchange factor (GEF) activity of neuroepithelial transforming gene 1 (Net1) and several other GEFs. Additionally, Rac1 may activate c-Jun N-terminal kinase (JNK), which phosphorylates Net1A and promotes its nuclear export. Net1A in the cytoplasm may promote RhoA activation. Conversely, active RhoA may inhibit Rac1 via actions of Rho-associated kinase (ROCK).

Figure 2

A brief schematic review of the role of RhoA in DDR: upon genotoxic stress, ataxia telangiectasia-mutated (ATM) and flap structure-specific endonuclease 1 (FEN1) are mobilized to activate RhoA, and this activation is also closely associated with ROS. In these processes, the participation of Rac1 and Rho-specific GEFs (especially, Net1A) may also be critical. Downstream of RhoA, mitogen-activated protein kinases (MAPKs) (especially, p38) and ROCKs seem to mediate cell arrest for DNA repair.