EXPLORING THE FUNCTIONS OF LONG NON-CODING RNA TERRA IN THE REGULATION OF TELOMERE MAINTENANCE IN Leishmania major

• Grant number: 24/20110-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Maria Isabel Nogueira Cano
• Grantee: Leilane Silva de Oliveira
• Host 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

TERRA (Telomeric Repeat-Containing RNA) is a non-coding RNA transcribed from the subtelomeric regions of the C-rich strand, playing an important role in regulating telomere structure and function. It is present in various eukaryotes, including humans and yeasts. Recent findings from our group indicate that TERRA in Leishmania major, one of the etiological agents of leishmaniasis, may influence telomere dynamics through the formation of R-loops, whose presence is significantly increased in the infective forms of the parasite. TERRA expression in these parasites appears to be controlled by base J, a hypermodified thymine abundantly found in telomeres and subtelomeric regions. Base J acts as an epigenetic marker, regulating the activity of RNA polymerase II and directly influencing telomeric transcription. Its biosynthesis and maintenance depend on the proteins JBP1 and JBP2, which play essential roles in this process. In Leishmania, telomere maintenance is crucial for the parasites, as telomerase depletion progressively shortens telomeres, increases TERRA transcription, and disrupts their proliferation, survival, and infectivity. We hypothesize that alterations in telomere regulation, mediated by elements such as TERRA and base J, may also compromise parasite viability, making telomeres a promising therapeutic target against leishmaniases. Leishmaniases are a group of neglected parasitic diseases of medical importance in Brazil and worldwide. Current treatments have limited efficacy, are highly toxic, and lead to parasite resistance, highlighting the need for new therapeutic strategies. Therefore, this project aims to investigate how different TERRA transcripts interact with the telomeric machinery and determine how they influence telomere maintenance in L. major by identifying their interactors, thereby understanding their role in the parasite's survival and developmental cycle. To achieve this, we will use wild-type strains, strains depleted of the basic components of telomerase (TER and TERT), and strains lacking the base J biosynthesis proteins, JBP1 and JBP2.