Research Paper Volume 11, Issue 23 pp 11268—11313

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

Jaana van Gastel 1, 2, , Hanne Leysen 1, 2, , Paula Santos-Otte 3, , Jhana O. Hendrickx 1, 2, , Abdelkrim Azmi 2, , Bronwen Martin 4, , Stuart Maudsley 1, 2, ,

  • 1 Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
  • 2 Translational Neurobiology Group, Centre for Molecular Neuroscience, VIB, Antwerp, Belgium
  • 3 Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
  • 4 Faculty of Pharmaceutical, Veterinary and Biomedical Science, University of Antwerp, Antwerp, Belgium

received: September 4, 2019 ; accepted: November 18, 2019 ; published: December 3, 2019 ;

https://doi.org/10.18632/aging.102528
How to Cite

Copyright © 2019 van Gastel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

AP-MS: Affinity Purification Mass Spectrometry; ATM: Ataxia Telangiectasia Mutated; CPT: Camptothecin; DDR: DNA damage response; DRY: aspartic acid (Asp) - arginine (Arg) - tyrosine (Tyr); GIT2: G protein-coupled receptor kinase interacting transcript 2; GPCR: G protein-coupled receptor; H2O2: Hydrogen peroxide; KO: Knockout; PRKDC: DNA-protein kinase C; RLN3: relaxin 3; RXFP3: relaxin family peptide 3 receptor.