Evaluation of VHR and NPM proteins in DNA repair and proliferation of leukemic cells

• Grant number: 17/16491-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: January 01, 2018
• End date: July 31, 2022
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Fábio Luis Forti
• Grantee: Jessica Oliveira Farias
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leukemias are among the cancers of higher population incidence, both in adults and children, and their treatment is mainly medicated with agents capable of promoting DNA damage in order to destroy the leukemic cells. The mechanisms involved in the development of the disease are not yet fully understood, which means that the therapies used are still non-specific and limited. Some published works have reported the involvement of altered expression and/or mutations in the protein Nucleophosmin (NPM), which is a protein involved in maintaining genomic integrity. On the other hand, a differential expression of tyrosine phosphatases in different cells of the immune system has been described, correlating them with stage of differentiation and activation. These included atypical dual phosphatase VHR, which was recently shown by our group to interact physically and possibly chemically with NPM in cells submitted to conditions of genotoxic stress, but through mechanisms still unknown. In addition, other results from our group suggest a direct involvement of VHR in DNA repair mechanisms after damage induced by ionizing or non-ionizing radiation, possibly leading to a functional regulation of NPM through its differential dephosphorylation on tyrosines. Thus, this work aims to investigate correlations between the expression of VHR and NPM proteins in leukemic cell lines (HL-60, THP-1, MOLT-4 and Jurkat) against genotoxic stress caused by gamma radiation and doxorubicin, And the impact of overexpression and/or silencing of these proteins on related DNA repair mechanisms and cell proliferation/survival. Certainly, the knowledge raised in this work may contribute to the understanding of the involvement of these two proteins (VHR and NPM) in the tumorigenic potential of these cells, as well as in the other proteins involved with the pathways in which these proteins act and/or regulate, That can be invested in the future in the improvement of diagnostics, monitoring and therapies applied to the different types of Leukemias. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAGALHAES, YULI T.; FARIAS, JESSICA O.; SILVA, LUIZ E.; FORTI, FABIO L.. GTPases, genome, actin: A hidden story in DNA damage response and repair mechanisms. DNA Repair, v. 100, APR 2021. (18/01753-6, 17/16491-4, 15/03983-0, 17/01451-7)

RUSSO, LILIAN CRISTINA; FARIAS, JESSICA OLIVEIRA; FORTI, FABIO LUIS. DUSP3 maintains genomic stability and cell proliferation through modulation of the NER pathway and cell cycle regulatory proteins. CELL CYCLE, v. 19, n. 12, MAY 2020. (17/16491-4, 15/03983-0, 18/01753-6)