Ivestigation of the effects of induced replicative stress over HJURP levels and its potential use as an adjuvant therapy

Abstract

Astrocytomas along with glioblastomas (GBM) represent the most frequent type of primary brain tumor, GBM being the most frequent and agressive among them. We have shown that the protein HJURP (Holliday Junction Recognizing Protein) is upregulated in different grades of astrocytoma and GBM and it is related to worse prognosis. Recent investigations indicate a correlation between HJURP overexpression and less DNA double strand breaks in replicative stress situations induced by hydroxyurea and camptothecin and, interestingly, a reduction of HJURP levels in these cells. This project intends to analyze the response of astrocytoma cells overexpressing HJURP under replicative stress situations induced by aphidicolin, seeking confirmation about its effects over HJURP levels in these cells and characterize the mechanisms associated with the downregulation. We will evaluate the kinetics associated with HJURP levels under insult, and if its reduction is mediated by ubiquitination of the protein. At last, we will assess whether or not replicative stress induction increases GBM cells overexpressing HJURP sensitivity towards TMZ, with a combined treatment between the drugs. In that manner, this project intends to complement our studies about the role of HJURP providing proliferative competence to astrocytoma cells, better characterizing the role of this protein, which has been described as an important biomarker to both progression and resistance of this tumor type.