title: A Genome-Wide Screen with Nicotinamide to Identify Sirtuin-Dependent Pathways in Saccharomyces cerevisiae.
abstract: Sirtuins are evolutionarily conserved NAD-dependent deacetylases that catalyze the cleavage of NAD(+) into nicotinamide (NAM), which can act as a pan-sirtuin inhibitor in unicellular and multicellular organisms. Sirtuins regulate processes such as transcription, DNA damage repair, chromosome segregation, and longevity extension in yeast and metazoans. The founding member of the evolutionarily conserved sirtuin family, SIR2, was first identified in budding yeast. Subsequent studies led to the identification of four yeast SIR2 homologs HST1, HST2, HST3, and HST4. Understanding the downstream physiological consequences of inhibiting sirtuins can be challenging since most studies focus on single or double deletions of sirtuins, and mating defects in SIR2 deletions hamper genome-wide screens. This represents an important gap in our knowledge of how sirtuins function in highly complex biological processes such as aging, metabolism, and chromosome segregation. In this report, we used a genome-wide screen to explore sirtuin-dependent processes in Saccharomyces cerevisiae by identifying deletion mutants that are sensitive to NAM. We identified 55 genes in total, 36 of which have not been previously reported to be dependent on sirtuins. We find that genome stability pathways are particularly vulnerable to loss of sirtuin activity. Here, we provide evidence that defects in sister chromatid cohesion renders cells sensitive to growth in the presence of NAM. The results of our screen provide a broad view of the biological pathways sensitive to inhibition of sirtuins, and advance our understanding of the function of sirtuins and NAD(+) biology.
authors.affiliation: Department of Biology, The Catholic University of America, Washington, D.C. 20064 choy@cua.edu basraim@nih.gov.
authors.forename: John S
authors.initials: JS
authors.lastname: Choy
authors.affiliation: Department of Biology, The Catholic University of America, Washington, D.C. 20064.
authors.forename: Bayan
authors.initials: B
authors.lastname: Qadri
authors.affiliation: Department of Biology, The Catholic University of America, Washington, D.C. 20064.
authors.forename: Leah
authors.initials: L
authors.lastname: Henry
authors.affiliation: Department of Biology, The Catholic University of America, Washington, D.C. 20064.
authors.forename: Kunal
authors.initials: K
authors.lastname: Shroff
authors.affiliation: Department of Biology, The Catholic University of America, Washington, D.C. 20064.
authors.forename: Olatomiwa
authors.initials: O
authors.lastname: Bifarin
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 choy@cua.edu basraim@nih.gov.
authors.forename: Munira A
authors.initials: MA
authors.lastname: Basrai
mesh_terms: D001692:Biological Transport; D004260:DNA Repair; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D009154:Mutation; D009536:Niacinamide / Q000378:metabolism*; D021381:Protein Transport; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D009536:Niacinamide; D037761:Sirtuins