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EMU awarded in the process 2018/18007-5: TissueFAXS microscope

Grant number: 19/06039-2
Support Opportunities:Multi-user Equipment Program
Start date: May 01, 2019
End date: April 30, 2026
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Nicolas Carlos Hoch
Grantee:Nicolas Carlos Hoch
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/18007-5 - Protein ADP-ribosylation: DNA damage signalling and impacts on human health, AP.JP
As informações de acesso ao Equipamento Multiusuário são de responsabilidade do Pesquisador responsável
EMU web page:http://ca.iq.usp.br/novo/paginas_view.php?idPagina=69
Type of equipment:Caracterização de Materiais - Microscopia ótica - Fluorescência
Manufacturer: Tissue Gnostics
Model: TissueFAXS

Abstract

Genomic instability is the main driving force for cancer onset and progression, underlies the ageing process and is associated with neurodegenerative disease. Protein post-translational modification by NAD+-derived ADP-ribose moieties plays central roles in orchestrating the cellular DNA damage response, but most of the human enzymes that catalyse this modification, as well as the hydrolases that remove it, remain to be characterised. We have identified a role for the mono-ADP-ribosyl transferases PARP3, PARP9 and the ubiquitin ligase DTX3L in a common pathway that protects cells from a poorly defined form of DNA damage induced by the stabilization of G4 quadruplexes, a form of DNA secondary structure. Importantly, both PARP9 and DTX3L are recurrently overexpressed in diffuse large B-cell lymphomas (DLBCL) and mutations in histone H4 lysine 91, the target site for DTX3L ubiquitination, cause a human genetic disorder characterised by increased spontaneous DNA damage and neurodevelopmental defects. The first objective of this proposal is to characterise this novel DNA repair pathway in detail, with the aim of identifying disease mechanisms that may guide the future development of treatment options for these disorders. In a parallel project, we will study ARH3, another gene involved in a genetic neurological disorder, which encodes an ADP-ribosyl hydrolase whose cellular functions in response to DNA damage are currently unknown.In this proposal we combine research into fundamental biological mechanisms and human genetics, to shed light on the role of protein ADP-ribosylation in the DNA damage response and human disease. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)

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)
SERRANO-BENITEZ, ALMUDENA; WELLS, SOPHIE E.; DRUMMOND-CLARKE, LYLAH; RUSSO, LILIAN C.; THOMAS, JOHN CHRISTOPHER; LEAL, GIOVANNA A.; FARROW, MARK; EDGERTON, JAMES MICHAEL; BALASUBRAMANIAN, SHANKAR; YANG, MING; et al. Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity. EMBO Journal, v. 42, n. 18, p. 19-pg., . (18/18007-5, 19/06039-2)
LATANCIA, MARCELA T.; MORENO, NATALIA C.; LEANDRO, GIOVANA S.; RIBEIRO, VICTORIA CHAVES; DE SOUZA, IZADORA; MARTINS VIEIRA, WILLIAM KLEBER; BASTOS, ANDRE UCHIMURA; HOCH, NICOLAS CARLOS; ROCHA, CLARISSA R. R.; MENCK, CARLOS F. M.. DNA polymerase eta protects human cells against DNA damage induced by the tumor chemotherapeutic temozolomide. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, v. 878, p. 11-pg., . (19/06039-2, 13/08028-1, 18/10061-0, 19/19435-3)