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Function of the MRE11, DNA2 and EXO1 nucleases in DNA end resection and double-strand breaks repair in Trypanosoma brucei

Grant number: 19/01895-8
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2019
Effective date (End): July 31, 2023
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Maria Carolina Quartim Barbosa Elias Sabbaga
Grantee:Ricardo Obonaga Gómez
Host 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):22/16039-2 - Function of the MRE11 and EXO1 nucleases and BLM helicase in antigenic variation in Trypanosoma brucei, BE.EP.PD


DNA Double Strand Breaks (DSBs) are one of the most toxic forms of DNA damage. These can arise accidentally during normal cell metabolism or after exposure of cells to DNA-damaging agents. Failure to repair them can result in genomic instability, a characteristic of cancer cells. In eukaryotes, DSBs are repaired by Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ). In HR and Microhomology-Mediated End Joining (MMEJ) (a type of NHEJ Ku heterodimer-Independent), the 5´ DNA strands of the DSBs are nucleolytically degraded through a process termed DNA end resection. This process, which generate 32-ended single-stranded DNA tails with different lengths of homology sequences, is critical for repair pathway choice by HR or MMEJ and checkpoint signaling. In most eukaryotes, repair by HR and MMEJ is conserved, including Trypanosoma brucei, the parasite responsible for African human trypanosomiasis, a disease which is fatal if untreated. In this parasite, DNA end resection is not defined. Thus, we intend to characterize the function of the major nucleases in DNA resection and repair of DSBs. For this, the nucleases MRE11, DNA2 and Exo1 will be silenced in different configurations and both the resection and repair of DSBs generated by the treatment with ionizing radiation or by the activity of the I-Scel enzyme, will be evaluated. In addition, parameters such as nuclear localization using fluorescence microscopy and DNA-bound proteins; length and resection rate using the single molecule analysis of resected tracks and qPCR and; functions of these nucleases in repair pathway choice (HR or MMEJ) using a reporter system will be evaluated. In addition, we will determine if there are differences in the participation of these nucleases in the DNA end resection and repair of DSBs cell cycle dependent. Finally, we will characterize the function of these nucleases in the DNA end resection of DSBs at a subtelomeric locus. (AU)

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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)
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, . (17/18719-2, 18/12364-0, 15/10580-0, 14/02978-0, 14/24170-5, 19/01895-8, 16/50050-2, 14/13375-5)

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