Oxidative stress and DNA repair in Xeroderma Pigmentosum Variant human cells exposed to UVA radiation.

• Grant number: 22/16390-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2023
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: James Eduardo Lago Londero
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM

Abstract

Patients of the autosomal recessive disease Xeroderma Pigmentosum Variant (XPV) are highly sensitive to solar ultraviolet (UV) radiation and are at increased risk of skin cancer. This clinical phenotype is due to the cellular absence of functional polymerases eta (pol eta), which are proteins responsible for replicating damaged DNA in a process called translesion synthesis. Notably, the nucleotide excision repair (NER) pathway, which is responsible for removing UV-induced DNA damage, is functional in XPV cells, in contrast to what occurs in cells from classic Xeroderma Pigmentosum patients, who are NER deficient. However, the efficiency of the NER pathway is affected when replicating XPV cells are exposed to UVA radiation and this is related to greater replicative and oxidative stress. In this project, we aim to elucidate the mechanisms that connect the high oxidative stress to the inhibition of the NER pathway in XPV cells irradiated with UVA, through comparative tests involving replicating and quiescent cells. Specifically, through the use of quiescent and replicating cells, we will evaluate the relationship between oxidative stress and NER inhibition, as well as investigate the essential protein of the NER pathway - Replication Protein A (RPA) - as a molecular target of the oxidative stress in UVA-irradiated XPV cells. Moreover, we will assess whether the occurrence of the 8-oxoguanine lesion, the main oxidatively generated lesion, is primarily responsible for the increase in C>A type mutations observed previously in UVA-induced XPV cells. Thus, by identifying possible critical molecular mechanisms for the sensitivity of XPV patients to solar radiation, we ultimately aim to contribute to the development of precise therapeutic interventions that contribute to a better quality of life for XPV patients and the general population.