The role of XPG endonuclease in nuclear RNA transcription and in the maintenance of mitochondrial genome

• Grant number: 17/18781-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): January 01, 2018
• Effective date (End): April 30, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: Davi Mendes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 14/15982-6 - Consequences of repair deficiencies in damaged genome, AP.TEM

Abstract

DNA contains the genetic information and is constantly exposed to endogenous or exogenous genotoxic agents that can cause damage, eventually leading to mutagenesis or cell death. The most common endogenous agents are Reactive Oxygen Species (ROS), originated mainly by processes such as cellular respiration and inflammation. These agents oxidize bases, sugars, phosphates and cause single (SSBs) or double (DSBs) strand breaks in the DNA molecule. During evolution, cells have developed DNA repair systems that correct DNA damage. Dysfunctions in these systems may result in human syndromes, which are important for understanding processes such as aging and neurodegeneration, linked mainly to the accumulation of damage in both the nuclear and mitochondrial DNA. In addition, the decrease in RNA transcription by DNA damage has been one of the hypotheses to explain such degenerative processes. The present project aims to analyze the roles of the XPG protein in the transcriptional blockage by ROS and in the repair of damage of the mitochondrial genome. Among the transcriptional problems to be investigated, we plan to search for the formation of RNA:DNA hybrids, so called R-loops, during DNA damage blockage of transcription. We also intend to evaluate how cells with different levels of deficiency in XPG can maintain the stability of the mitochondrial genome. These data will be correlated with DNA damage consequences, such as cell death. To attend these goals, we will use isogenic cell lines 94RD27, 94RD27 WT, 94RD27 RJ1 and 94RD27 RJ2. The 94RD27 cell line is from a XP/CS patient (with neurodegenerative clinical phenotype) with a mutation that encodes a truncated XPG protein, the second cell line which was complemented with wild-type gene, and the third and fourth cell lines that were partially complemented with XPG alleles encoding the whole XPG protein but with no endonucleolytic activity (from Brazilian XP patients with no neurodegenerative clinical phenotypes). Thus, we hope to contribute to the understanding of how aging and neurodegeneration emerge from problems related to DNA repair. (AU)

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)

MONTEIRO DE ASSIS, LEONARDO VINICIUS; MENDES, DAVI; SILVA, MATHEUS MOLINA; KINKER, GABRIELA SARTI; PEREIRA-LIMA, ISABELLA; MORAES, MARIA NATHALIA; MARTINS MENCK, CARLOS FREDERICO; DE LAURO CASTRUCCI, ANA MARIA. Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1867, n. 10, OCT 2020. (14/27287-0, 19/19435-3, 13/24337-4, 17/24615-5, 12/50214-4, 18/16511-8, 17/26651-9, 17/18781-0, 18/14728-0, 17/24217-0)

DE ASSIS, LEONARDO VINICIUS MONTEIRO; MORAES, MARIA NATHALIA; MENDES, DAVI; SILVA, MATHEUS MOLINA; MENCK, CARLOS FREDERICO MARTINS; CASTRUCCI, ANA MARIA DE LAURO. Loss of Melanopsin (OPN4) Leads to a Faster Cell Cycle Progression and Growth in Murine Melanocytes. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 43, n. 3, p. 1436-1450, DEC 2021. (18/16511-8, 17/24615-5, 17/26651-9, 17/18781-0, 19/19435-3, 18/14728-0, 17/24217-0)

MONTEIRO DE ASSIS, LEONARDO VINICIUS; LACERDA, JOSE THALLES; MORAES, MARIA NATHALIA; DOMINGUEZ-AMOROCHO, OMAR ALBERTO; KINKER, GABRIELA SARTI; MENDES, DAVI; SILVA, MATHEUS MOLINA; MARTINS MENCK, CARLOS FREDERICO; SARAIVA CAMARA, NIELS OLSEN; DE LAURO CASTRUCCI, ANA MARIA. Melanopsin (Opn4) is an oncogene in cutaneous melanoma. COMMUNICATIONS BIOLOGY, v. 5, n. 1, p. 15-pg., 2022-05-13. (19/19435-3, 19/25129-2, 17/24217-0, 17/26651-9, 18/16511-8, 12/50214-4, 18/14728-0, 17/24615-5, 17/18781-0, 20/04524-8, 13/24337-4, 17/16711-4)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

MENDES, Davi. Analysis of the role of the XPG endonuclease in nuclear transcription and mitochondrial genome integrity. 2024. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.