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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

ATR Kinase Is a Crucial Player Mediating the DNA Damage Response in Trypanosoma brucei

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Marin, Paula Andrea [1] ; Obonaga, Ricardo [1] ; Pavani, Raphael Souza [1] ; da Silva, Marcelo Santos [1] ; de Araujo, Christiane Bezerra [1] ; Lima, Andre Arruda [1] ; Avila, Carla Cristi [1] ; Cestari, Igor [2, 3] ; Machado, Carlos Renato [4] ; Elias, Maria Carolina [1]
Total Authors: 10
[1] Butantan Inst, Ctr Toxins Immune Response & Cell Signaling CET, Lab Cell Cycle LCC, Sao Paulo - Brazil
[2] McGill Univ, Inst Parasitol, Montreal, PQ - Canada
[3] McGill Univ, Div Expt Med, Montreal, PQ - Canada
[4] Univ Fed Minas Gerais, Inst Biomed Sci, Biochem & Immunol Dept, Belo Horizonte, MG - Brazil
Total Affiliations: 4
Document type: Journal article
Web of Science Citations: 0

DNA double-strand breaks (DSBs) are among the most deleterious lesions that threaten genome integrity. To address DSBs, eukaryotic cells of model organisms have evolved a complex network of cellular pathways that are able to detect DNA damage, activate a checkpoint response to delay cell cycle progression, recruit the proper repair machinery, and resume the cell cycle once the DNA damage is repaired. Cell cycle checkpoints are primarily regulated by the apical kinases ATR and ATM, which are conserved throughout the eukaryotic kingdom. Trypanosoma brucei is a divergent pathogenic protozoan parasite that causes human African trypanosomiasis (HAT), a neglected disease that can be fatal when left untreated. The proper signaling and accuracy of DNA repair is fundamental to T. brucei not only to ensure parasite survival after genotoxic stress but also because DSBs are involved in the process of generating antigenic variations used by this parasite to evade the host immune system. DSBs trigger a strong DNA damage response and efficient repair process in T. brucei, but it is unclear how these processes are coordinated. Here, by knocking down ATR in T. brucei using two different approaches (conditional RNAi and an ATR inhibitor), we show that ATR is required to mediate intra-S and partial G1/S checkpoint responses. ATR is also involved in replication fork stalling, is critical for H2A histone phosphorylation in a small group of cells and is necessary for the recruitment and upregulation of the HR-mediated DNA repair protein RAD51 after ionizing radiation (IR) induces DSBs. In summary, this work shows that apical ATR kinase plays a central role in signal transduction and is critical for orchestrating the DNA damage response in T. brucei. (AU)

FAPESP's process: 17/18719-2 - Structural analysis of the origin recognition complex (ORC) in Trypanosoma brucei using cryo-electron microscopy and single-particle analysis
Grantee:Marcelo Santos da Silva
Support type: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 18/12364-0 - Expression, purification and initial characterization of a new RPA-like protein in Trypanosoma brucei
Grantee:André Arruda Lima
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 15/10580-0 - Characterization of intra-S checkpoint in Trypanosoma cells
Grantee:Maria Carolina Quartim Barbosa Elias Sabbaga
Support type: Regular Research Grants
FAPESP's process: 14/02978-0 - Functional analysis of RPA complex in Trypanosoma cruzi and its involvement with telomeric DNA
Grantee:Raphael Souza Pavani
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 14/24170-5 - DNA replication dynamics in Trypanosoma cruzi: licensing and replication rate characterization
Grantee:Marcelo Santos da Silva
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 19/01895-8 - Function of the MRE11, DNA2 and EXO1 nucleases in DNA end resection and double-strand breaks repair in Trypanosoma brucei
Grantee:Ricardo Obonaga Gómez
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 16/50050-2 - How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites?
Grantee:Maria Carolina Quartim Barbosa Elias Sabbaga
Support type: Research Projects - Thematic Grants
FAPESP's process: 14/13375-5 - Replication origins in trypanosomes
Grantee:Christiane Bezerra de Araujo
Support type: Scholarships in Brazil - Post-Doctorate