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Characterization of the ATR kinase of Leishmania major and its role in DNA replication stress signaling

Grant number: 16/16454-9
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): April 01, 2017
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Luiz Ricardo Orsini Tosi
Grantee:Gabriel Lamak Almeida da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:16/50050-2 - How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites?, AP.TEM
Associated scholarship(s):19/20731-6 - Characterization of the ATR kinase of Leishmania major and its role in DNA replication stress signaling., BE.EP.DD


Little is known about the kinase ATR role in the homeostasis of the genome of primitive eukaryotes, such as trypanosomatids. In other eukaryotes, ATR participates in the signaling of DNA damaged structures, mainly through the phosphorylation of Chk1 and subsequent cell cycle arrest. The main objective of this project is to investigate the conservation of ATR kinase in Leishmania and explore its contribution to the signaling of DNA replicative stress. The expected results include determining the distribution of ATR and its involvement in cell cycle progression in cells under replicative stress. We also expect to analyze the effect of altered levels of ATR (overexpression or knock-down) in the signaling of replicative stress and in the parasite genome stability. The unusual size of the ATR gene (9.6 Kb) limits the possibilities of genetic manipulation of the parasite using established strategies. Thus, we propose the development of a strategy that combines the DiCre-recombinase and CRISPR/cas9 systems for the conditional knockout of ATR. (AU)

Scientific publications
(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)
DAMASCENO, JEZIEL D.; OBONAGA, RICARDO; SILVA, GABRIEL L. A.; REIS-CUNHA, JOAO L.; DUNCAN, SAMUEL M.; BARTHOLOMEU, DANIELLA C.; MOTTRAM, JEREMY C.; MCCULLOCH, RICHARD; TOSI, LUIZ R. O. Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania. Nucleic Acids Research, v. 46, n. 22, p. 11835-11846, DEC 14 2018. Web of Science Citations: 2.

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