Study of mitochondrial H2O2 mediated redox signaling in XPC deficient models

• Grant number: 22/01155-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2023
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Thiago de Souza Freire
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM

Abstract

XPC is a protein involved in the early stages of the global genome nucleotide excision repair pathway (GG-NER). However, deficient models of XPC have phenotypes that are not apparently related to DNA damage and therefore imply that XPC has functions other than those performed in the GG-NER pathway. Among the most evident phenotypes presented by XPC deficiency are apparent redox signaling dysfunction, changes in mitochondrial functions, and an imbalance in gene expression caused by changes in the levels of important transcription factors, such as p53. Thus, the diversity of phenotypes presented by XPC deficiency provides a great opportunity to investigate the relationships that occur in different signaling pathways that involve the response to DNA damage, redox signaling and mitochondrial bioenergetics. Our group demonstrated that XPC deficiency causes significant mitochondrial changes that determine the main phenotypes presented by this model. More recently, we have advanced the mechanistic understanding by determining that XPC deficiency causes profound changes in gene expression as a result of unbalanced p53 levels and H2O2 production. Our model points to a central role of H2O2 in redox signaling pathways leading to the phenotype presented by XPC deficiency. Thus, this project proposes to advance in the construction of a global mechanistic understanding of how XPC deficiency initiates H2O2 production, which intermediate factors are essential for maintaining this pathway and at which intervention points this phenotype can be reversed.