Molecular and functional investigation of the interactions between DUSP3 with nuclear proteins and its implications in DNA repair mechanisms

• Grant number: 15/03983-0
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2015
• End date: March 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Fábio Luis Forti
• Grantee: Fábio Luis Forti
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Andreza Cândido Matias ; Lilian Cristina Russo Vieira

Abstract

The high expression and nuclear activity of protein phosphatases is mostly attributed to the serine / threonine phosphatases (S/TP). Only a few protein tyrosine phosphatases (PTP) acting on nuclear biochemical and biological events have been characterized. One of the PTP sub- families whose substrates are very diverse and little explored is the dual specificity phosphatases (DUSP), more specifically the sub- group of atypical enzymes (aDUSPs). Some of these enzymes are able to dephosphorylate tyrosine and threonine or serine residues of protein substrates, such as the mitogen-activated kinases (MAPK). However, biological functions that are not mediated by MAPKs have been identified as dependent on some DUSPs, which in fact should be attributed to still unknown substrates of these enzymes. For example, DUSP3 or VHR, is a dual specificity phosphatase that in addition to inhibiting MAPK for the fine tune control of cell proliferation, has key functions in DNA repair mechanisms identified by our group, which probably is due to the still unknown substrates of this enzyme. Our hypothesis was confirmed by two recent publications that DUSP3 physically interacts with nuclear proteins directly and indirectly involved with DNA repair, as Nibrin, Nucleolin, Nucleophosmin and Ribonucleoprotein C. But how this interaction is and how DUSP3 is promoting the dephosphorylation of these new target proteins we still do not know. Also, what is the functionality of these new interactions DUSP3, that is, how they are affecting biological mechanisms controlled by these four proteins are open questions that need further investigation. Finally, how the functional alteration of these four proteins by silencing DUSP3 is affecting specific mechanisms of DNA repair , such as the nucleotide excision repair (NER) of DNA damaged by ultraviolet radiation, is also part of the problem raised by this project. In sum, we want to go deep in the knowledge of DUSP enzymes in relation to new biological functions through getting better knowledge of their protein substrates and molecular mechanisms of their interactions. (AU)

Scientific publications

(14)

(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)

PEREIRA, NADINE RANIERI; RUSSO, LILIAN CRISTINA; FORTI, FABIO LUIS. UV Radiation-induced Impairment of Cellular Morphology and Motility is Enhanced by DUSP3/VHR Loss and FAK Activation. Cell Biochemistry and Biophysics, v. 79, n. 2, JAN 2021. (15/03983-0, 18/01753-6)

DA SILVA, LUIZ EDUARDO; RUSSO, LILIAN CRISTINA; FORTI, FABIO LUIS. Overactivated Cdc42 acts through Cdc42EP3/Borg2 and NCK to trigger DNA damage response signaling and sensitize cells to DNA-damaging agents. Experimental Cell Research, v. 395, n. 2, p. 12-pg., 2020-10-15. (15/03983-0, 18/01753-6)

ESPINHA, GISELE; OSAKI, JULIANA HARUMI; COSTA, ERICO TOSONI; FORTI, FABIO LUIS. Inhibition of the RhoA GTPase Activity Increases Sensitivity of Melanoma Cells to UV Radiation Effects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, v. 2016, p. 14-pg., 2016-01-01. (11/05822-3, 10/09453-0, 15/03983-0)

RUSSO, LILIAN CRISTINA; FARIAS, JESSICA OLIVEIRA; MINAYA FERRUZO, PAULT YEISON; MONTEIRO, LUCAS FALCAO; FORTI, FABIO LUIS. Revisiting the roles of VHR/DUSP3 phosphatase in human diseases. Clinics, v. 73, n. 1, 2018. (15/03983-0)

MAGALHAES, YULI T.; CARDELLA, GIOVANNA D.; FORTI, FABIO L.. Exoenzyme C3 transferase lowers actin cytoskeleton dynamics, genomic stability and survival of malignant melanoma cells under UV-light stress. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 209, AUG 2020. (17/01451-7, 19/05736-1, 15/03983-0, 18/01753-6)

RUSSO, LILIAN C.; FERRUZO, PAULT Y. M.; FORTI, FABIO L.. Nucleophosmin Protein Dephosphorylation by DUSP3 Is a Fine-Tuning Regulator of p53 Signaling to Maintain Genomic Stability. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, MAR 11 2021. (18/01753-6, 15/03983-0)

ESPINHA, GISELE; OSAKI, JULIANA HARUMI; COSTA, ERICO TOSONI; FORTI, FABIO LUIS. Inhibition of the RhoA GTPase Activity Increases Sensitivity of Melanoma Cells to UV Radiation Effects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2016. (15/03983-0, 10/09453-0, 11/05822-3)

RUSSO, LILIAN C.; ARAUJO, CHRISTIANE B.; IWAI, LEO K.; FERRO, EMER S.; FORTI, FABIO L.. A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells. JOURNAL OF PROTEOMICS, v. 151, n. SI, p. 24-32, JAN 16 2017. (13/07467-1, 15/03983-0)

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)

MAGALHAES, YULI T.; SILVA, GISELE E. T.; OSAKI, JULIANA H.; ROCHA, CLARISSA R. R.; FORTI, FABIO L.. RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 8, AUG 19 2020. (11/05822-3, 10/09453-0, 18/01753-6, 15/03983-0, 10/20506-8, 17/01451-7)

TORRES, THOMPSON E. P.; RUSSO, LILIAN C.; SANTOS, ALEXSANDRO; MARQUES, GABRIELA R.; MAGALHAES, YULI T.; TABASSUM, SARTAJ; FORTI, FABIO L.. Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1861, n. 7, p. 1879-1894, JUL 2017. (15/03983-0, 11/05822-3)

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)

RUSSO, LILIAN CRISTINA; FARIAS, JESSICA OLIVEIRA; MINAYA FERRUZO, PAULT YEISON; MONTEIRO, LUCAS FALCAO; FORTI, FABIO LUIS. Revisiting the roles of VHR/DUSP3 phosphatase in human diseases. Clinics, v. 73, p. 7-pg., 2018-01-01. (15/03983-0)

RUSSO, LILIAN C.; ARAUJO, CHRISTIANE B.; IWAI, LEO K.; FERRO, EMER S.; FORTI, FABIO L.. A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells. JOURNAL OF PROTEOMICS, v. 151, p. 9-pg., 2017-01-16. (13/07467-1, 15/03983-0)