Protein ADP-ribosylation: DNA damage signalling and impacts on human health

• Grant number: 18/18007-5
• Support type: Research Grants - Young Investigators Grants
• Duration: April 01, 2019 - March 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal researcher: Nicolas Carlos Hoch
• Grantee: Nicolas Carlos Hoch
• Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated grant(s): 20/05317-6 - Inhibition of the viral macrodomain as a strategy for Coronavirus treatment, AP.R; 19/06039-2 - EMU awarded in the process 2018/18007-5: TissueFAXS microscope, AP.EMU
• Associated scholarship(s): 22/10783-1 - Recruitment and activation of the PARP9-DTX3L heterodimer in response to DNA damage, BP.MS; 22/10947-4 - Advanced technical support in cell biology and microscopy techniques, BP.TT; 22/04866-1 - The PARP9-DTX3L heterodimer and DNA damage-induced interferon signalling, BP.IC; + associated scholarships 21/10124-5 - Designing Sars-Cov-2 Mono-ADP-ribosyl hydrolase Enzyme Inhibitors: A New Class of Antiviral Agents?, BP.PD; 22/03340-6 - General technical assistance and generation of knockout cell lines using CRISPR/Cas9 technology, BP.TT; 20/02701-0 - Cellular functions of the ADP-ribosyl hydrolase ARH3 in the maintenance of genomic stability, BP.DD; 19/25914-1 - Role of PARP9/DTX3L-dependent H4K91 ubiquitination in the DNA damage response, BP.DD; 19/06769-0 - The PARP9-DTX3L heterodimer and DNA damage-induced interferon signalling, BP.IC - associated scholarships

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 catalyze this modification, as well as the hydrolases that remove it, remain to be characterized. 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 characterized by increased spontaneous DNA damage and neurodevelopmental defects. The first objective of this proposal is to characterize 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)

Scientific publications

(4)

(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)

HOCH, NICOLAS C.. Host ADP-ribosylation and the SARS-CoV-2 macrodomain. BIOCHEMICAL SOCIETY TRANSACTIONS, v. 49, n. 4, p. 1711-1721, AUG 2021. (18/18007-5, 20/05317-6)

NICOLAS C. HOCH; LUIS M. POLO. ADP-ribosylation: from molecular mechanisms to human disease. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 2019-12-13. (18/18007-5)

HOCH, NICOLAS C.; POLO, LUIS M.. ADP-ribosylation: from molecular mechanisms to human disease. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 1, 2020. (18/18007-5)

RUSSO, LILIAN CRISTINA; TOMASIN, REBEKA; MATOS, ISAAC ARAUJO; MANUCCI, ANTONIO CARLOS; SOWA, SVEN T.; DALE, KATIE; CALDECOTT, KEITH W.; LEHTIO, LARI; SCHECHTMAN, DEBORAH; MEOTTI, FLAVIA C.; et al. The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. Journal of Biological Chemistry, v. 297, n. 3, SEP 2021. (18/18007-5, 18/14898-2, 19/26767-2)