Genetic Map of the Mammalian Cell Response to Environmental Stress

A wide variety of environmental stressors, from pesticides to common anticancer chemotherapies, result in protein damage. This damage underlies diseases such as cancer and neurodegeneration, and when caused by prescription drugs, leads to toxic side effects limiting usage. To cope with these proteotoxic stresses, cells

express molecular chaperones, co-chaperones, and a variety of additional support proteins – collectively referred to as the proteostasis network (PN) – that are integral for the proper synthesis, folding, stability and degradation of the cellular proteome. Thus, understanding the regulation and function of the PN is critically important in

understanding its role in the interface between disease susceptibility and exposure to environmental stressors. We previously developed a broadly applicable framework and online resource (FIREWORKS) to interrogate biological networks using unbiased genetic screens. Using our FIREWORKS framework, we mapped the

constituents of and relationships between stress response pathways in human cells coping with growth-related molecular stresses revealing a network of 146 genes with vital functions spanning diverse stress contexts. Here, we propose to expand this resource to create an unbiased and global map of the response to environmental

proteotoxic stress. We will integrate our cutting-edge chemical-genetic screening platform with our FIREWORKS computational pipeline to identify components, function, and regulatory nodes critical for the cellular response to environmental stressors. In parallel, we will identify transcriptional changes that occur immediately and

throughout longer periods of environmental stress exposure, to provide a framework for understanding cellular adaptation to these stressors. Collectively, this map will serve as a major resource for the research community, provide a more complete understanding of cellular environmental stress response programs, and lead to insights

into the large variability in the risk of adverse events that arise from exposure to these insults.