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Study of actin and tubulin cytoskeleton involvement in DNA damage repair of gliomas after gamma radiation treatment

Grant number: 19/05736-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2019
Effective date (End): March 31, 2020
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Deborah Schechtman
Grantee:Giovanna Duo Cardella
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Glioblastoma (GBM) is the most common primary brain tumor, characterized for advanced necrosis, increased cellular proliferation and resistance to the clinically adopted radio and chemotherapies. It is known that GBMs have steady cytoskeleton dynamics, with increased expression of proteins actin and tubulin, which is intimately related to GBM migration, proliferation and invasiveness capacity, despite the fact that the p53 tumor suppressor gene is mutated in 30% of the tumors. There are scarce studies correlating the cytoskeleton with DNA damage repair pathways, but preliminary studies of our laboratory showed that the destabilization of both actin and tubulin cytoskeleton enhanced the sensibility of glioblastomas to ionizing radiation. The combination of F-actin or microtubules depolymerization with ionizing radiation treatment reduced the cell proliferation and the survival, with different responses to each cell line: actin disruption provoked additive effects in p53 mutated cell line, while microtubules depolymerization provoked a synergistic and more evident effect. Considering the proliferative response of glioblastomas and sensitivity to the combined treatments, in this work we intend to investigate the cytoskeleton roles in the DNA damage repair, evaluating the expression and localization of proteins pH2AX and 53BP1, dedicated to foci formation of DNA repair, after cell exposure to different types of cytoskeleton destabilization drugs followed by gamma radiation treatment. Also, we intend to evaluate the expression and phosphorylation of other DDR pathway proteins in the same conditions and investigate these treatments influence in global DNA repair. Thus we expect to reaffirm actin and tubulin cytoskeleton as a potential therapeutic target when combined with conventional genotoxic treatments to tackle glioblastomas resistance in clinics.