How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites?

• Grant number: 16/50050-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2016
• End date: October 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Agreement: BBSRC, UKRI
• Principal Investigator: Maria Carolina Quartim Barbosa Elias Sabbaga
• Grantee: Maria Carolina Quartim Barbosa Elias Sabbaga
• Principal researcher abroad: Richard McCulloch
• Institution abroad: University of Glasgow, Scotland
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Pesquisadores principais: Luiz Ricardo Orsini Tosi
• Associated scholarship(s): 16/16454-9 - Characterization of the ATR kinase of Leishmania major and its role in DNA replication stress signaling, BP.DD; 16/18192-1 - Replication stress response characterization in the protozoan Leishmania: the role of the ATR kinase, BP.PD; 16/18191-5 - Characterizing stress response of DNA replication in the protozoan Leishmania: the case of replication-transcription conflict, BP.PD

Abstract

Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. (tritryps) present different in their life cycles as well as in their strategy for vertebrate infection. These differences in core biology are influenced by the ability of the parasites to maintain and alter their genome, leading to adaptive changes in gene expression. Gene expression is organized almost exclusively as polycistronic transcription, where every gene is expressed from one of a small number of a multigene units meaning that RNA Polymerase needs to traverse unusually long distances. The nature of transcription in each genome must predispose the parasites to pronounced replication stress due to collision between the replication and transcription machineries, leading to DNA replication fork stalling. In such stress conditions, the halted DNA fork is recognized by kinases ATM and ATR, which initiate a signaling cascade that mediates the appropriate response to the blockade. The nature of the replication stress signaling or the mechanisms of response are not the same in the tritryps and differences in genome architecture in the tritryps may be related to differing strategies used to resolve replication stress due to clashes with transcription. Specifically, it might be predicted that T. brucei activates dormant origins in conditions of stress, whereas T. cruzi and Leishmania resolve the stalled forks using recombination/amplification. We aim to determine if replication-transcription clashes are the main cause of the different genome architectures, and to reveal and compare the strategies used to resolve a stalled DNA replication forks in the parasites. (AU)

Scientific publications

(21)

(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)

CALDERANO, SIMONE GUEDES; NISHIYAMA JUNIOR, MILTON YUTAKA; MARINI, MARJORIE; NUNES, NATHAN DE OLIVEIRA; REIS, MARCELO DA SILVA; PATANE, JOSE SALVATORE LEISTER; DA SILVEIRA, JOSE FRANCO; DA CUNHA, JULIA PINHEIRO CHAGAS; ELIAS, MARIA CAROLINA. Identification of Novel Interspersed DNA Repetitive Elements in the Trypanosoma cruzi Genome Associated with the 3 ` UTRs of Surface Multigenic Families. GENES, v. 11, n. 10, OCT 2020. (13/07467-1, 16/50050-2)

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, DEC 22 2020. (17/18719-2, 18/12364-0, 15/10580-0, 14/02978-0, 14/24170-5, 19/01895-8, 16/50050-2, 14/13375-5)

DA SILVA, MARCELO S.; CAYRES-SILVA, GUSTAVO R.; VITARELLI, MARCELA O.; MARIN, PAULA A.; HIRAIWA, PRISCILA M.; ARAUJO, CHRISTIANE B.; SCHOLL, BRUNO B.; AVILA, ANDREA R.; MCCULLOCH, RICHARD; REIS, MARCELO S.; et al. Transcription activity contributes to the firing of non-constitutive origins in African trypanosomes helping to maintain robustness in S-phase duration. SCIENTIFIC REPORTS, v. 9, DEC 6 2019. (15/10580-0, 17/07693-2, 17/18719-2, 16/17775-3, 14/24170-5, 16/50050-2, 13/07467-1, 14/13375-5)

ROSON, JULIANA NUNES; VITARELLI, MARCELA DE OLIVEIRA J.; COSTA-SILVA, HELLIDA MARINA; PEREIRA, KAMILLE SCHMITT; PIRES, DAVID DA SILVA; LOPES, LETICIA DE SOUSA; CORDEIRO, BARBARA; KRAUS, AMELIE; CRUZ, KARIN NAVARRO TOZZI; CALDERANO, SIMONE GUEDES; et al. 2B.V demarcates divergent strand-switch regions, some tDNA loci, and genome compartments in Trypanosoma cruzi and affects parasite differentiation and host cell invasio. PLOS PATHOGENS, v. 18, n. 2, FEB 2022. (18/15553-9, 16/50050-2, 17/06104-3, 19/04483-2, 19/16033-1, 13/07467-1, 19/19834-5)

SILVA, MARCELO S. DA; VITARELLI, MARCELA O.; VIALA, VINCENT LOUIS; TSANTARLIS, KATHERINE; PIRES, DAVID DA SILVA; FRANCO, THIAGO A.; DE AZEVEDO, INACIO L. M. J.; ELIAS, MARIA CAROLINA; TONELLI, RENATA R.. Clues on the dynamics of DNA replication in Giardia lamblia. Journal of Cell Science, v. 136, n. 10, p. 13-pg., 2023-05-01. (17/07693-2, 20/10277-3, 18/14432-3, 13/07467-1, 14/24170-5, 19/02918-1, 20/00694-6, 16/50050-2, 19/10753-2)

DE ARAUJO, CHRISTIANE BEZERRA; CHAGAS DA CUNHA, JULIA PINHEIRO; INADA, DAVI TOSHIO; DAMASCENO, JEZIEL; JERONIMO LIMA, ALEX RANIERI; HIRAIWA, PRISCILA; MARQUES, CATARINA; GONCALVES, EVONNILDO; NISHIYAMA-JUNIOR, MILTON YUTAKA; MCCULLOCH, RICHARD; et al. Replication origin location might contribute to genetic variability in Trypanosoma cruzi. BMC Genomics, v. 21, n. 1, JUN 22 2020. (13/07467-1, 14/24170-5, 16/50050-2, 14/13375-5)

DA SILVA, MARCELO S.; VITARELLI, MARCELA O.; SOUZA, BRUNO F.; ELIAS, MARIA CAROLINA. Comparative Analysis of the Minimum Number of Replication Origins in Trypanosomatids and Yeasts. GENES, v. 11, n. 5, MAY 2020. (13/07467-1, 14/24170-5, 16/50050-2, 17/18719-2, 17/07693-2)

CALDERANO, SIMONE GUEDES; NISHIYAMA JUNIOR, MILTON YUTAKA; MARINI, MARJORIE; NUNES, NATHAN DE OLIVEIRA; REIS, MARCELO DA SILVA; PATANE, JOSE SALVATORE LEISTER; DA SILVEIRA, JOSE FRANCO; DA CUNHA, JULIA PINHEIRO CHAGAS; ELIAS, MARIA CAROLINA. Identification of Novel Interspersed DNA Repetitive Elements in the Trypanosoma cruzi Genome Associated with the 3 ' UTRs of Surface Multigenic Families. GENES, v. 11, n. 10, p. 20-pg., 2020-10-01. (16/50050-2, 13/07467-1)

PAVANI, RAPHAEL S.; DE LIMA, LOYZE P.; LIMA, ANDRE A.; FERNANDES, CARLOS A. H.; FRAGOSO, STENIO P.; CALDERANO, SIMONE G.; ELIAS, MARIA CAROLINA. Nuclear export of replication protein A in the nonreplicative infective forms of Trypanosoma cruzi. FEBS Letters, v. 594, n. 10, p. 1596-1607, MAY 2020. (16/50050-2, 14/02978-0, 18/14432-3, 18/21785-0, 13/07467-1)

DE ARAUJO, CHRISTIANE BEZERRA; DE LIMA, LOYZE PAOLA; CALDERANO, SIMONE GUEDES; DAMASCENO, FLAVIA SILVA; SILBER, ARIEL M.; ELIAS, MARIA CAROLINA. Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of the Trypanosoma cruzi Life Cycle and Blocks Parasite Infectivity. Antimicrobial Agents and Chemotherapy, v. 63, n. 5, MAY 2019. (13/07467-1, 16/06034-2, 17/16553-0, 16/50050-2, 14/13375-5)

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. (14/00751-9, 17/07092-9, 14/06824-8, 13/00570-1, 16/16454-9, 16/50050-2)

COSTA-SILVA, HELLIDA MARINA; RESENDE, BRUNO CARVALHO; UMAKI, ADRIANA CASTILHOS SOUZA; PRADO, WILLIAN; DA SILVA, MARCELO SANTOS; VIRGILIO, STELA; MACEDO, ANDREA MARA; PENA, SERGIO DANILO JUNHO; TAHARA, ERICH BIRELLI; TOSI, LUIZ RICARDO ORSINI; et al. DNA Topoisomerase 3 alpha Is Involved in Homologous Recombination Repair and Replication Stress Response in Trypanosoma cruzi. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, MAY 13 2021. (14/24170-5, 18/14398-0, 13/07467-1, 16/50050-2)

LIMA, ALEX R. J.; DE ARAUJO, CHRISTIANE B.; BISPO, SALOE; PATANE, JOSE; SILBER, ARIEL M.; ELIAS, M. CAROLINA; DA CUNHA, JULIA P. C.. Nucleosome landscape reflects phenotypic differences in Trypanosoma cruzi life forms. PLOS PATHOGENS, v. 17, n. 1, JAN 2021. (18/15553-9, 19/19690-3, 18/14432-3, 16/50050-2, 13/07467-1)

DA SILVA, MARCELO SANTOS; HOVEL-MINER, GALADRIEL A.; BRIGGS, EMMA M.; ELIAS, MARIA CAROLINA; MCCULLOCH, RICHARD. Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes. PLOS PATHOGENS, v. 14, n. 11, NOV 2018. (13/07467-1, 14/24170-5, 17/18719-2, 16/50050-2)

ALVES, CERES LUCIANA; REPOLES, BRUNO MARCAL; DA SILVA, MARCELO SANTOS; MENDES, ISABELA CECILIA; MARIN, PAULA ANDREA; NASCIMENTO AGUIAR, PEDRO HENRIQUE; SANTOS, SELMA DA SILVA; FRANCO, GLORIA REGINA; MACEDO, ANDREA MARA; JUNHO PENA, SERGIO DANILO; et al. The recombinase Rad51 plays a key role in events of genetic exchange in Trypanosoma cruzi. SCIENTIFIC REPORTS, v. 8, SEP 6 2018. (13/07467-1, 14/24170-5, 16/50050-2)

MARIN, PAULA ANDREA; DA SILVA, MARCELO SANTOS; PAVANI, RAPHAEL SOUZA; MACHADO, CARLOS RENATO; ELIAS, MARIA CAROLINA. Recruitment kinetics of the homologous recombination pathway in procyclic forms of Trypanosoma brucei after ionizing radiation treatment. SCIENTIFIC REPORTS, v. 8, MAR 29 2018. (13/07467-1, 15/10580-0, 14/24170-5, 16/50050-2)

DE LIMA, LOYZE P.; CALDERANO, SIMONE G.; DA SILVA, MARCELO S.; DE ARAUJO, CHRISTIANE B.; VASCONCELOS, ELTON J. R.; IWAI, LEO K.; PEREIRA, CLAUDIO A.; FRAGOSO, STENIO P.; CAROLINA ELIAS, M.. Ortholog of the polymerase theta helicase domain modulates DNA replication in Trypanosoma cruzi. SCIENTIFIC REPORTS, v. 9, FEB 27 2019. (13/07467-1, 14/24170-5, 14/13375-5, 16/50050-2)

DE ARAUJO, CHRISTIANE B.; CALDERANO, SIMONE G.; ELIAS, MARIA CAROLINA. The Dynamics of Replication in Trypanosoma cruzi Parasites by Single-Molecule Analysis. Journal of Eukaryotic Microbiology, v. 66, n. 3, p. 514-518, MAY-JUN 2019. (13/07467-1, 16/50050-2, 14/13375-5)

DA SILVA, MARCELO S.; PAVANI, RAPHAEL S.; DAMASCENO, JEZIEL D.; MARQUES, CATARINA A.; MCCULLOCH, RICHARD; ORSINI TOSI, LUIZ RICARDO; ELIAS, MARIA CAROLINA. Nuclear DNA Replication in Trypanosomatids: There Are No Easy Methods for Solving Difficult Problems. Trends in Parasitology, v. 33, n. 11, p. 858-874, NOV 2017. (13/07467-1, 15/10580-0, 14/24170-5, 16/50050-2)

CRISPIM, MARCELL; DAMASCENO, FLAVIA SILVA; HERNANDEZ, AGUSTINO; BARISON, MARIA JULIA; SAUTER, ISMAEL PRETTO; PAVANI, RAPHAEL SOUZA; MOURA, ALEXANDRE SANTOS; FURUSHO PRAL, ELIZABETH MIEKO; CORTEZ, MAURO; ELIAS, MARIA CAROLINA; et al. The glutamine synthetase of Trypanosoma cruzi is required for its resistance to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection. PLoS Neglected Tropical Diseases, v. 12, n. 1, JAN 2018. (13/07467-1, 16/06034-2, 15/10580-0, 14/10443-0, 16/50050-2)

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, p. 18-pg., 2020-12-22. (14/02978-0, 14/24170-5, 14/13375-5, 18/12364-0, 19/01895-8, 16/50050-2, 17/18719-2, 15/10580-0)