The contribution of lipid regulators Sre1 and Dga1 to the genotoxic stress response in fission yeast
Start Date
2023 3:40 PM
Location
Alter Hall 207
Abstract
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 examined the genomic and physiological consequences of disruptions to two lipid regulator genes, SREBPF1 and DGAT1, frequently mutated in human cancers. We used the Catalogue of Somatic Mutations in Cancer (COSMIC) to interrogate the link between mutation profiles and mean age at time of sequencing (MATS), tissue distribution, and primary tumor histology. Employing Cancer-Related Analysis of Variants Toolkit (CRAVAT) and Variant Effect Scoring Tool (VEST) algorithms, we tested for driver and passenger mutations. We observe the majority of mutations in SREBPF1 and DGAT1 affecting large intestine, liver, skin, and stomach tissues. In SREBPF1, there is a mutation cluster localized to the HLH domain that mediates binding to DNA, thereby potentially interfering with gene expression. In DGAT1, the MBOAT domain harbors multiple mutations that likely disrupt enzyme function. Moreover, differences in MATS reveal aging trajectories that correlate with specific tissue or tumor types, thereby indicating cellular contexts that promote accelerated aging. Since the products of these genes show functional homology in fission yeast, we examined how lipid deregulation by a knock-out enzyme (Dga1DGAT1-DGAT2) and a transcription factor (Sre1SREBF1) influence the response to genotoxic stress in fission yeast. Using microscopy quantification of lipid staining, we observe abnormal homeostatic control of lipid levels in cells lacking Dga1 and Sre1. These phenotypes are enhanced in sub-lethal doses of DNA damage (UV-C light) and are associated with altered cell fitness and viability. Furthermore, in response to genotoxicity, these lipid regulator mutants exhibit abnormal cell dimensions and cell segmentation, which suggest disruption to cell cycle dynamics. These data indicate functional mechanisms that may contribute to the deregulated metabolic and physiological environments of prematurely aged cells in human cancers.
The contribution of lipid regulators Sre1 and Dga1 to the genotoxic stress response in fission yeast
Alter Hall 207
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 examined the genomic and physiological consequences of disruptions to two lipid regulator genes, SREBPF1 and DGAT1, frequently mutated in human cancers. We used the Catalogue of Somatic Mutations in Cancer (COSMIC) to interrogate the link between mutation profiles and mean age at time of sequencing (MATS), tissue distribution, and primary tumor histology. Employing Cancer-Related Analysis of Variants Toolkit (CRAVAT) and Variant Effect Scoring Tool (VEST) algorithms, we tested for driver and passenger mutations. We observe the majority of mutations in SREBPF1 and DGAT1 affecting large intestine, liver, skin, and stomach tissues. In SREBPF1, there is a mutation cluster localized to the HLH domain that mediates binding to DNA, thereby potentially interfering with gene expression. In DGAT1, the MBOAT domain harbors multiple mutations that likely disrupt enzyme function. Moreover, differences in MATS reveal aging trajectories that correlate with specific tissue or tumor types, thereby indicating cellular contexts that promote accelerated aging. Since the products of these genes show functional homology in fission yeast, we examined how lipid deregulation by a knock-out enzyme (Dga1DGAT1-DGAT2) and a transcription factor (Sre1SREBF1) influence the response to genotoxic stress in fission yeast. Using microscopy quantification of lipid staining, we observe abnormal homeostatic control of lipid levels in cells lacking Dga1 and Sre1. These phenotypes are enhanced in sub-lethal doses of DNA damage (UV-C light) and are associated with altered cell fitness and viability. Furthermore, in response to genotoxicity, these lipid regulator mutants exhibit abnormal cell dimensions and cell segmentation, which suggest disruption to cell cycle dynamics. These data indicate functional mechanisms that may contribute to the deregulated metabolic and physiological environments of prematurely aged cells in human cancers.
