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

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)