Cyclin 5 functions in Trypanosoma cruzi: finding its canonical (cell cycle regulation) and non-canonical functions

• Grant number: 22/02243-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2022
• End date: July 31, 2024
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Simone Guedes Calderano
• Grantee: Evelin Mariani Gonçalves
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Trypanosoma cruzi is the causative agent of Chagas disease, endemic to Latin America and a public health problem in Brazil. This disease still depends on treatment with the same drugs as in the 1970s, and the search for new drugs is a challenge due to the resistance and persistence of T. cruzi to treatments. During its complex life cycle, T. cruzi transits between the insect vector and the mammalian host, encountering different conditions on its way to which its life forms are adapted. Among these life forms, amastigotes (in the mammalian host) and epimastigotes (in the insect vector) can replicate, expand the population of T. cruzi and differentiate into infective forms that are unable to replicate. Blocking proliferation in the transition to infective forms is a landmark event and nutritional stress and environmental factors are known to trigger this block, but how it is regulated remains unknown. CDKs and cyclins regulate cell proliferation and entry into quiescence in model eukaryotes. In T. cruzi, CDKs homologs, CRKs (Cdc2-related kinase), and cyclins act on cell cycle control and replication control is an important factor involved in the persistence of this parasite. Cyclin 5 stands out among the cyclins for being able to interact with the two characterized CRKs (CRK1 and CRK3) and for presenting phosphorylation sites that are modulated during metacyclogenesis in trypomastigotes after contact with the extracellular matrix. Preliminary data from our laboratory suggest that cyclin 5 plays a role in the control of cell proliferation, acting in the S phase of the cell cycle, since: (i) its expression is modulated during the cell cycle, with peak expression in the S phase and (ii) cyclin 5 can interact with the DNA replication protein Orc1/Cdc6. Thus, this proposal aims to identify the role of cyclin 5 in cell cycle regulation through the identification of its interactors (using TurboID) and to evaluate its potential non-canonical role throughout the life cycle of T. cruzi. Since the modulation of cell proliferation is an important factor involved in the resistance and persistence of post-treatment infection, understanding the role of proliferation regulatory proteins is fundamental to unravel the mechanisms of cell resistance and in the identification of new therapeutic targets. (AU)