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Study of role of DNA polymerase eta in cellular responses and carcinogenesis induced by ultraviolet light a

Grant number: 18/26555-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2019
Effective date (End): April 30, 2021
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Nadja Cristhina de Souza Pinto
Grantee:Natália Cestari Moreno
Home 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

UVA light (UVA) is an environmental agent that induces DNA (cyclobutene pyrimidine dimers - CPDs, and oxidized bases) and protein damage, which are related to exposure outcome such as skin aging and carcinogenesis. The important functions of Nucleotide Excision Repair (NER) and Translesion Synthesis (TLS) to protect against UV-induced skin cancer is evidenced by the rare hereditary disease Xeroderma Pigmentosum (XP), where patients caring mutations in genes involved in NER and TLS display a 1,000-fold higher skin cancer incidence. In particular, patients with XP Variant (XP-V), with defective TLS due to pol eta mutations, show remarkable sensitivity to UVA light. In addition to DNA damage, protein oxidation and mitochondrial dysfunction have also been shown to play important roles in the carcinogenic process; however, their participation in XP-V carcinogenesis is unknown. In this context, this project has four specific aims: 1) to elucidate the participation of CPDs in UVA-induced cell death in XP-V and pol eta complemented cells, 2) to evaluate the differential response to UVA-induced redox processes in presence and absence of pol eta, 3) to understand the mechanism by which NER is attenuated after UVA exposure and 4) the contribution of UVA light-induced DNA damages in the skin carcinogenesis of normal and XP people. We also propose to develop an innovative methodology for induction of cellular transformation after UVA irradiation. This approach will allow a direct demonstration of the role of increased mutagenesis in the process of tumorigenesis in human XP cells, as well as provide a tool to test potential ways to reduce tumor formation in these patients, aiming to improve their life quality.