Investigation of the involvement of CENP-A in the DNA repair facilitation promoted by HJURP

• Grant number: 20/09013-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2021
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Valeria Valente
• Grantee: Leticia Tuzi Leopoldo
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Glioblastoma (GBM) is the most frequent, aggressive and lethal primary brain tumor. Among the characteristics that make it so grave are the high resistance and proliferative capacity of tumor cells, which cause recurrences and lead patients to death in approximately 14 months after diagnosis. We have previously demonstrated that the HJURP protein is highly overexpressed in GBM and contributes to worse prognoses of patients. HJURP was extensively characterized as the chaperone of the H3 histone variant, CENP-A, being responsible for its incorporation into the centromeres. The entry of CENP-A in the centromeric nucleosomes favors a more relaxed state of chromatin and the formation of functional kinetochores. Previous data from our group revealed that HJURP also works in the repair of double-stranded DNA breaks. HJURP and CENP-A were recruited to break sites and the presence of HJURP favored chromatin decompression around the rupture, facilitating lesion processing. We also observed that high levels of HJURP contribute to the resistance of GBM cells to radiation and to the response of patients to radiotherapy. In this context, we believe that HJURP and CENP-A act interdependently in the establishment of this competence. However, our preliminary data were not conclusive. Therefore, this project aims to verify if CENP-A is, indeed, required for the DNA repair facilitation promoted by HJURP. For that, we will evaluate different parameters of DNA repair capacity when CENP-A is suppressed. Thus, we intend to advance in the understanding of HJURP/CENP-A mechanisms of action during DNA repair and to verify if CENP-A is also a biomarker of patients' responsiveness to IR.