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
(9)
(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)
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.
Web of Science Citations: 5.