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Studies about the effect of knocking out and overexpressing the Telomerase RNA component in L. major development and survival

Grant number: 19/25985-6
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): February 01, 2020
Effective date (End): November 30, 2023
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal Investigator:Maria Isabel Nogueira Cano
Grantee:Beatriz Cristina Dias de Oliveira
Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated research grant:18/04375-2 - Studies about the biogenesis and composition of the Leishmania spp. ribonucleoprotein complex and its regulation, AP.TEM

Abstract

Leishmaniases are infectious diseases with high mortality and incidence rate caused by parasites of the genus Leishmania, Trypanosomatidae family. The disease has a wide geographical distribution and presents different clinical manifestations. The lack of efficient control and disease treatment classifies Leishmaniases as neglected diseases, urgently requiring the discovery of new therapeutic targets. Telomeres, the physical ends of eukaryotic chromosomes maintained by telomerase, are of great interest since they play fundamental roles in genome maintenance and cell proliferation. Telomerase is a ribonucleoprotein minimally composed of TERT (Telomerase Reverse Transcriptase), and a lncRNA, TER (Telomerase RNA), which contains the template sequence that TERT uses to replicate the telomeric DNA during telomere replication. Recent studies show that in spite of telomere elongation TER has other biological functions. Its secondary structure present domains that control TERT nucleotide insertion, sequence recognition, and binding of accessory proteins. Recently, the Leishmania TER component (LeishTER) was identified and partially characterized, although little is known about its biogenesis and functions. Thus, the present work aims to study and better understand the role played by LeishTER in parasite proliferation and survival by generating LeishTER overexpressing parasites and LeishTER knockout parasites using the CRISPR-Cas9 system developed by Beneke et al. (2017). We intend to verify whether the overexpression and loss of the TER component affect telomere maintenance by telomerase, metacyclogenesis, and parasite infectivity. It will also be analyzed the function of LeishTER in parasites overexpressing PINX1, a natural telomerase inhibitor, which sequester TERT from the ribonucleoprotein telomerase complex. Unlike the TERT component, TER from other eukaryotes is an organism-specific molecule that shares conservation in their secondary structure and primary functions. Thus, TER can be considered potential targets for the development of specific anti-parasite therapies. (AU)