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Project title: Characterization of small molecule inhibitors to target the heterodimeric endonuclease mus81-eme1 in cancer cells
Interstrand crosslinks (ICLs) are one of the most cytotoxic DNA lesions. ICLs repair mechanism involves several proteins from three different DNA repair pathways: Nucleotide Excision Repair (NER), Homologous Recombination (HR) and Translesion Synthesis (TLS). ICL repair proteins are potential drug targets to treat cancer with poor response to traditional genotoxic drugs. MUS81-EME1 is an obligatory heterodimeric endonuclease belonging to the XPF/MUS81 family of nucleases, in which plays a role in ICL repair and HR. MUS81-EME1 is an essential protein in telomerase-negative and ALT (Alternative Lengthening of Telomeres)-positive cancer cells. ALT mechanism is an HR-based mechanism of telomere maintenance that is present in 10-15% of human tumors and has high prevalence in bone and soft tissues malignancies. We are interested in discover selective inhibitors of MUS81-EME1 and inhibitors that target both XPF-ERCC1 and MUS81-EME1. To identify and characterize small molecules inhibitors for MUS81-EME1 Our laboratory developed a High Throughput Screening (HTS) based on fluorescence nuclease assay. Preliminary data from HTS screening identified initial hits that are being validated in dose-response curves. My role in this project is to validate and to optimize compounds obtained from HTS-hits capable to inhibit MUS81-EME1 and/or XPF-ERCC1 endonucleases and, therefore, to test whether these compounds will be able to target HR in ALT and other mammary cancer cells.
2002 – 2006 BSc Biological Sciences with Dr. Carlos R. Machado, Federal University of Minas Gerais
2007 – 2008 MSc with Dr. Carlos R. Machado, Federal University of Minas Gerais
2008-2013 PhD with Dr. Carlos R. Machado, Federal University of Minas Gerais
2011-2012 Sabbatical year with Dr. Richard McCulloch at Wellcome Trust Centre for Molecular Parasitology – University of Glasgow
2009 Evaluation of genotoxicity – Short course (15 hours) – Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
2009 Survival, apoptosis and DNA damage detection assays – Short course (30 hours) –Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
2014 EBI-course Genomics for working with pathogens (40 hours) – Fundação Oswaldo Cruz, Centro de Pesquisa René Rachou, Belo Horizonte, MG, Brazil.
2014 Publicase Intensive Workshop: writing a biomedical scientific article in one week (40 hours) – Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
2014 Basic course on fluorescence and confocal microscopy (20 hours) – Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
2015 Basic course on Perl programming language (30 hours) – Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. 2015 Molecular aspects of chemotherapy, resistance and immunoprophylaxis in trypanosomatids (30 hours) – Fundação Oswaldo Cruz, Centro de Pesquisa René Rachou, Belo Horizonte, MG, Brazil.
2016 Training on sequence-based HLA genotyping through SeCore® system (40 hours) – Simile Medicina Diagnostica, Belo Horizonte, MG, Brazil.
2005-2006 Analysis of DNA polymorphisms in translesion synthesis DNA polymerases from Trypanosoma cruzi.
2006-2010 Characterization of DNA polymerase Rev1 from Trypanosoma cruzi.
2009-2013 Evaluation of the role of histone chaperone Asf1 in tripanosomatid DNA damage response.
2011-2012 Studies of homologous recombination mechanisms in Trypanosoma cruzi and Trypanosoma brucei.
2011-2013 Functional characterization of Nucleotide Excision Repair from Trypanosoma brucei.
2011-2015 Comparative analysis of nuclear and mitochondrial DNA repair efficiencies between bloodstream and procyclic forms of T. brucei.
2013 Unveiling benznidazole’s mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi.
2014-2015 Characterization of gene expression control proteins from S. mansoni as potential vaccine targets.
2014-2015 Validation of in silico-defined SmZF1 DNA binding sites by ChIP-Seq analysis.
2016 Application of sequencing-based techniques in clinical diagnostic of EGFR mutational status and HLA genotyping.
2016-2017 Characterization of small molecule inhibitors to target the heterodimeric endonuclease Mus81-Eme1 in cancer cells.
2016-2017 ScCdc5 phosphoregulation of ScMus81-Mms4 substrate selectivity.
Leishmania major and Trypanosoma cruzi present distinct DNA damage responses. Garcia JB*, Rocha JP*, Costa-Silva HM, Alves CL, Machado CR**, Cruz AK**. Molecular & Biochemical Parasitology. 2016 May;207(1):23-32. doi: 10.1016. *(These authors contributed equally to this work). **(Corresponding authors).
Nucleotide excision repair in Trypanosoma brucei: specialization of transcription-coupled repair due to multigenic transcription. Machado CR*, Vieira-da-Rocha JP*, Mendes IC, Rajão MA, Marcello L, Bitar M, Drummond MG, Grynberg P, Oliveira DA, Marques C, Van Houten B, McCulloch R.Mol Microbiol. 2014 May;92(4):756-76. doi: 10.1111/mmi.12589. *(These authors contributed equally to this work).
Effect of ionizing radiation exposure on Trypanosoma cruzi ubiquitin-proteasome system. Cerqueira PG, Passos-Silva DG, Vieira-da-Rocha JP, Mendes IC, de Oliveira KA, Oliveira CF, Vilela LF, Nagem RA, Cardoso J, Nardelli SC, Krieger MA, Franco GR, Macedo AM, Pena SD, Schenkman S, Gomes DA, Guerra-Sá R, Machado CR. Mol Biochem Parasitol. 2017 Mar;212:55-67. doi: 10.1016
Unveiling benznidazole’s mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi. Rajão MA, Furtado C, Alves CL, Passos-Silva DG, de Moura MB, Schamber-Reis BL, Kunrath-Lima M, Zuma AA, Vieira-da-Rocha JP, Garcia JB, Mendes IC, Pena SD, Macedo AM, Franco GR, de Souza-Pinto NC, de Medeiros MH, Cruz AK, Motta MC, Teixeira SM, Machado CR. Environ Mol Mutagen. 2014 May;55(4):309-21. doi: 10.1002/em.21839.
Characterization of two different Asf1 histone chaperones with distinct cellular localizations and functions in Trypanosoma brucei. Pascoalino B, Dindar G, Vieira-da-Rocha JP, Machado CR, Janzen CJ, Schenkman S. Nucleic Acids Res. 2014 Mar;42(5):2906-18. doi: 10.1093/nar/gkt1267.
Overview of DNA Repair in Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major.Passos-Silva DG, Rajão MA, Nascimento de Aguiar PH, Vieira-da-Rocha JP, Machado CR, Furtado C. J Nucleic Acids. 2010 Oct 4;2010:840768. doi: 10.4061/2010/840768.