Determination of mutational signatures by chemotherapeutic agents in glioblastoma cells deficient in translesion synthesis DNA polymerases

• Grant number: 23/09586-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2023
• End date: May 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Agreement: Netherlands Organisation for Scientific Research (NWO)
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: Maria Carolina Fernandes dos Santos
• 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

Glioblastoma is the most aggressive type of tumor that affects the central nervous system (CNS), normally treated with temozolomide (TMZ) concomitantly with surgical resection and radiotherapy, and may also be used in combined therapies, such as with cisplatin (CP). However, among the resistance mechanisms to these chemotherapeutic agents, we find Translesion Synthesis (TLS) polymerases that bypasses DNA damage generated, neutralizing their cytotoxic effects. TLS can also result in tumor cells with increased mutations and with greater potential to develop acquired resistance to treatment. This work seeks to understand the role of Y-family polymerases involved in TLS, determining the occurrence of mutational signatures in glioblastoma cells deficient in Polymerase Kappa (Polº) and Polymerase Iota (Pol¹), through the evaluation of cell survival and genotoxic stress; analyzing how these cells replicate their damaged DNA; and identifying the pattern of mutation induced in these cells after treatment with TMZ and CP. From the determination of these signatures, we hope to contribute to etiological, diagnostic and treatment aspects of glioblastoma. (AU)