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Functional analysis of RPA complex in Trypanosoma cruzi and its involvement with telomeric DNA

Grant number: 14/02978-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2015
Effective date (End): March 31, 2019
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Maria Carolina Quartim Barbosa Elias Sabbaga
Grantee:Raphael Souza Pavani
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling, AP.CEPID
Associated scholarship(s):16/24255-6 - Defining post-translational modifications and interactors for Replication Protein A (RPA) from trypanosomatids associated with DNA damage., BE.EP.DR

Abstract

Chagas disease is caused by the protozoan Trypanosoma cruzi, afflicting several regions ofworld, with a primary focus in Latin America. Despite advances, approximately eight million people are infected with this disease. The study of the molecular biology of this parasite may facilitate the discovery of new therapies as well as assist in understanding the molecular evolution of eukaryotic organisms. The telomeric complex, responsible for the integrity and genomic stability, is formed by the interaction of DNA with proteins that are responsible for maintaining and protecting these terminals. The RPA complex in eukaryotes comprises a heterotrimer that participates in replication, repair, recombination and telomere maintenance. In mammals and yeast, the RPA complex is mainly involved with replication and repair in telomeres. Studies conducted by our group showed that RPA - 1 of T. cruzi interacts with telomeres in vivo in replicative and non-replicative forms and showed that, unlike other organisms, this protein has affinity for G -rich telomeric strand. Furthermore, structural analysis of RPA -1 protein shows significant differences when compared with RPA -1 from higher eukaryotes, such as the absence of 70N domain that interacts with repair machinery proteins. In Leishmania amazonensis, only RPA - 1 subunit was found interacting with telomeres. The absence of homologous proteins that interact with the telomere overhang on trypanosomes, specific interaction RPA -1- telomere, structural peculiarities of tripanossomatids RPA lead us to hypothesize that this protein plays a distinct role on the telomeres of this parasites, maybe involved in protection of telomeres. This project aims to understand the role of the RPA complex at the telomeres through experiments of RNAi silencing of RPA-1 and through complementation assay in yeasts. It also aims to initiate studies with the RPA - 2, to check the occurrence of the RPA trimerization in telomere, as well as new search for proteins that interacts with the complex performing immunoprecipitation assays, followed by mass spectrometry analysis. (AU)

Scientific publications (5)
(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)
MARIN, PAULA ANDREA; OBONAGA, RICARDO; PAVANI, RAPHAEL SOUZA; DA SILVA, MARCELO SANTOS; DE ARAUJO, CHRISTIANE BEZERRA; LIMA, ANDRE ARRUDA; AVILA, CARLA CRISTI; CESTARI, IGOR; MACHADO, CARLOS RENATO; ELIAS, MARIA CAROLINA. ATR Kinase Is a Crucial Player Mediating the DNA Damage Response in Trypanosoma brucei. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 8, DEC 22 2020. Web of Science Citations: 0.
PAVANI, RAPHAEL S.; DE LIMA, LOYZE P.; LIMA, ANDRE A.; FERNANDES, CARLOS A. H.; FRAGOSO, STENIO P.; CALDERANO, SIMONE G.; ELIAS, MARIA CAROLINA. Nuclear export of replication protein A in the nonreplicative infective forms of Trypanosoma cruzi. FEBS Letters, v. 594, n. 10 MAR 2020. Web of Science Citations: 0.
PAVANI, RAPHAEL SOUZA; VITARELLI, MARCELA O.; FERNANDES, CARLOS A. H.; MATTIOLI, FABIO F.; MORONE, MARIANA; MENEZES, MILENE C.; FONTES, MARCOS R. M.; CANO, MARIA ISABEL N.; ELIAS, MARIA CAROLINA. Replication Protein A-1 Has a Preference for the Telomeric G-rich Sequence in Trypanosoma cruzi. Journal of Eukaryotic Microbiology, v. 65, n. 3, p. 345-356, MAY-JUN 2018. Web of Science Citations: 2.
DA SILVA, MARCELO SANTOS; SEGATTO, MARCELA; PAVANI, RAPHAEL SOUZA; GUTIERREZ-RODRIGUES, FERNANDA; BISPO, VANDERSON DA SILVA; GENNARI DE MEDEIROS, MARISA HELENA; CALADO, RODRIGO TOCANTINS; ELIAS, MARIA CAROLINA; NOGUEIRA CANO, MARIA ISABEL. Consequences of acute oxidative stress in Leishmania amazonensis: From telomere shortening to the selection of the fittest parasites. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1864, n. 1, p. 138-150, JAN 2017. Web of Science Citations: 9.
PAVANI, RAPHAEL SOUZA; DA SILVA, MARCELO SANTOS; HENRIQUE FERNANDES, CARLOS ALEXANDRE; MORINI, FLAVIA SOUZA; ARAUJO, CHRISTIANE BEZERRA; DE MATTOS FONTES, MARCOS ROBERTO; SANT'ANNA, OSVALDO AUGUSTO; MACHADO, CARLOS RENATO; CANO, MARIA ISABEL; FRAGOSO, STENIO PERDIGAO; ELIAS, MARIA CAROLINA. Replication Protein A Presents Canonical Functions and Is Also Involved in the Differentiation Capacity of Trypanosoma cruzi. PLoS Neglected Tropical Diseases, v. 10, n. 12 DEC 2016. Web of Science Citations: 5.

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