Cellular functions of the ADP-ribosyl hydrolase ARH3 in the maintenance of genomic stability

• Grant number: 20/02701-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2020
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nicolas Carlos Hoch
• Grantee: Rafael Dias de Moura
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health, AP.JP

Abstract

Post-translational modification of proteins by ADP-ribosylation plays central roles in the cellular response to DNA damage. Few of the enzymes that catalyse this modification, and even fewer of the hydrolases that remove it, have been thoroughly characterised. The ADP-ribosyl hydrolase ARH3 has recently been shown to specifically remove ADP-ribose moieties attached to serines, which are the predominant target residue for DNA damage-induced protein ADP-ribosylation. Crucially, ARH3 mutations are associated with a rare genetic disorder characterised by neurodegenerative defects, suggesting a critical function in maintaining genomic stability in the brain. Here, we will generate ARH3 knockout cells using CRISPR/Cas9 technology and characterise DNA damage and repair phenotypes in these cells. In a complementary approach, we will purify ARH3-interacting proteins using biochemical methods. These studies will elucidate novel cellular functions of ARH3 in the DNA damage response and uncover new biological processes regulated by ADP-ribosylation. (AU)