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LIPID REGULATION BY DGA1, CUT6, AND SRE1 CONTRIBUTE TO THE GENOTOXIC STRESS RESPONSE IN FISSION YEAST


 Lipids are essential for cell growth and maintenance, intracellular signaling, and cellular energetics. When exposed to environmental insults, cells activate lipid metabolism programs that facilitate the response, recovery, and exit from stressful conditions. Failure to regulate lipid storage and utilization is associated with accelerated aging, which compounds genomic instability. In this study, we test the physiological consequences of disruptions to three lipid regulator genes frequently found to be mutated in human cancers. Since the products of these genes show functional homology in fission yeast, we examine how lipid deregulation by two enzymes (Dga1DGAT2 and Cut6ACC) and one transcription factor (Sre1SREBF1) influence the response to genotoxic stress in this organism. Using microscopy quantification of lipid staining, we observe abnormal homeostatic control of lipid levels in cells lacking Dga1, Cut6, and Sre1. These phenotypes are enhanced in sub-lethal doses of DNA damage (UV-C light) and are associated with altered cell fitness and proliferation. Furthermore, in response to genotoxicity, these lipid regulator mutants exhibit disrupted nuclear segregation, abnormal cell dimensions, and altered lifespan. These data suggest functional mechanisms that may contribute to the deregulated metabolic and physiological environments of prematurely aged cells and of tumors in human cancers.