DNA damage signaling pathways: mechanisms of regulation and cross-talk with cellular metabolism

• Grant number: 18/05417-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: October 01, 2018
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: José Renato Rosa Cussiol
• Grantee: José Renato Rosa Cussiol
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 22/15333-4 - Investigation on the role of the flavohemoglobin Yhb1 during genotoxic stress response on Saccharomyces cerevisiae yeast, BP.IC; 22/01752-5 - Investigation of the role of inositol and phosphate metabolism to the maintenance of genomic stability in Saccharomyces cerevisiae, BP.IC; 21/04887-6 - The role of inositol metabolism and its phosphorylate derivatives in the response to genomic damage in Saccharomyces cerevisiae, BP.DD; + associated scholarships 19/25497-1 - Characterization of the biological role of Opi1, a transcriptional repressor of phospholipid metabolism, in the regulation of the DNA damage signaling, BP.MS; 19/19155-0 - Characterization of a possible regulatory role of post-translational modifications in Dpb11 function during the DNA damage response in Saccharomyces cerevisiae, BP.IC; 19/03171-7 - Investigation of the biological role of Opi1, a repressor of inositol metabolism, during the DNA damage response in Saccharomyces cerevisiae, BP.IC - associated scholarships

Abstract

The genomic damage response is a network of cellular pathways which are responsible to sense, signal and activate chromatin repair and tolerance pathways. As part of this response, the protein quinase Mec1 (ATR in humans) coordinates the DNA damage checkpoint signaling pathway (DDC). Mec1 activation results in the regulation by phosphorylation of several proteins responsible to modulate many aspects of the cellular program with the ultimate goal to protect cells from genomic instability. Therefore, using the budding yeast Saccharomyces cerevisiae as a model organism, the aim of this project is to elucidate the molecular mechanisms that are involved in the modulation of Mec1 signaling and to understand how it connects with metabolic processes to promote cellular viability during genomic damage. More specifically, the present project consists of three interconnected specific aims which are going to investigate: 1 - The biological roles of Dpb11, a protein adaptor of Mec1 signaling, during the DNA damage response. 2 - The cross-talk between phospholipid metabolism and the DNA damage response and the role of Mec1 in this process. 3 - A possible regulatory role of the DDC in mitochondrial function. Together, this research program will contribute to a better understanding of the mechanisms involved in the prevention and adaption to genomic damage, one of the hallmarks of cancers and other diseases. (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)

ROSA CUSSIOL, JOSE RENATO; SOARES, BARBARA LUISA; BASTOS DE OLIVEIRA, FRANCISCO MEIRELLES. From yeast to humans: Understanding the biology of DNA Damage Response (DDR) kinases. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 1, 2020. (18/05417-0)

JOSÉ RENATO ROSA CUSSIOL; BÁRBARA LUÍSA SOARES; FRANCISCO MEIRELLES BASTOS DE OLIVEIRA. From yeast to humans: Understanding the biology of DNA Damage Response (DDR) kinases. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 2019-12-13. (18/05417-0)