The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

Abstract

DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in GIT2KO mice demonstrated that GIT2 expression affects the GPCR relaxin family peptide 3 receptor (RXFP3), and is thus a therapeutically-targetable system. RXFP3 and GIT2 play similar roles in metabolic aging processes. Gaining a detailed understanding of the RXFP3-GIT2 functional relationship could aid the development of novel anti-aging therapies. We determined the connection between RXFP3 and GIT2 by investigating the role of RXFP3 in oxidative stress and DDR. Analyzing the effects of oxidizing (H2O2) and DNA-damaging (camptothecin) stressors on the interacting partners of RXFP3 using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. RXFP3 expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of RXFP3 reduced phosphorylation of DNA damage marker H2AX, and repair protein BRCA1, moderating DNA damage. Our data suggests an RXFP3-GIT2 system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease

“…Loss of PRDX6 expression has previously been observed in aging cells and was shown to increase ROS production [59]. Furthermore, slight overexpression of RXFP3 resulted in an increased expression of PRDX6, indicating a synergistic role in the response to aging and oxidative stress [24]. Similar to PRDX6, SOD1 is also upregulated with RXFP3 overexpression [24].…”

“…Further investigation of the functions of this receptor has uncovered that RXFP3 might play a vital role in several aging-related disorders, as a connection has been found to several hallmarks of aging, such as oxidative stress and DNA damage response [24], similarly to the aging keystone GIT2 [6,7]. In addition, research by other groups has elucidated possible roles for RXFP3 in stress responses [25], anxiety [26], depression [26,27], feeding [15,[28][29][30], arousal [28], and alcohol addiction [31].…”

“…Van Gastel et al [24] identified superoxide dismutase 1 (SOD1), sirtuin 1 (SIRT1), Ras GTPase-activating, and peroxiredoxin 6 (PRDX6) among the proteins functionally interacting with RXFP3, indicating a role in oxidative stress responsiveness. Loss of PRDX6 expression has previously been observed in aging cells and was shown to increase ROS production [59].…”

The Role of Arginine Metabolism in Oral Tongue Squamous Cell Carcinoma

“…The most highly downregulated gene was relaxin family peptide receptor 3 ( RXFP3 ), a G-protein-coupled receptor that is thought to inhibit cAMP production and activate ERK1/2, PI3K- or PKC-dependent pathways [ 28 ]. Besides these roles, RXFP3 may possess a range of diverse signaling functions in the absence of its cognate ligand, all of which are uniquely related to the type of cell under investigation [ 28 , 29 ]. In age degeneration studies, elevated RXFP3 expression occurs in response to DNA damage whereby it indirectly regulates cellular degradation [ 29 ].…”

“…Besides these roles, RXFP3 may possess a range of diverse signaling functions in the absence of its cognate ligand, all of which are uniquely related to the type of cell under investigation [ 28 , 29 ]. In age degeneration studies, elevated RXFP3 expression occurs in response to DNA damage whereby it indirectly regulates cellular degradation [ 29 ]. That is, increased RXFP3 appears to attenuate the impact of DNA damage stress and may be associated with an augmented cellular protection from stress that enables cellular recovery.…”