Bypassing the requirement for an essential MYST acetyltransferase.
Histone acetylation is a key regulatory feature for chromatin that is established by opposing enzymatic activities of lysine acetyltransferases (KATs/HATs) and deacetylases (KDACs/HDACs). Esa1, like its human homolog Tip60, is an essential MYST family enzyme that acetylates histones H4 and H2A and other nonhistone substrates. Here we report that the essential requirement for ESA1 in Saccharomyces cerevisiae can be bypassed upon loss of Sds3, a noncatalytic subunit of the Rpd3L deacetylase complex. By studying the esa1∆ sds3∆ strain, we conclude that the essential function of Esa1 is in promoting the cellular balance of acetylation. We demonstrate this by fine-tuning acetylation through modulation of HDACs and the histone tails themselves. Functional interactions between Esa1 and HDACs of class I, class II, and the Sirtuin family define specific roles of these opposing activities in cellular viability, fitness, and response to stress. The fact that both increased and decreased expression of the ESA1 homolog TIP60 has cancer associations in humans underscores just how important the balance of its activity is likely to be for human well-being.
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, University of California at San Diego Moores Cancer Center, La Jolla, California 92093-0347.
Ana Lilia
AL
Torres-Machorro
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, University of California at San Diego Moores Cancer Center, La Jolla, California 92093-0347 lpillus@ucsd.edu.
Lorraine
L
Pillus
D000107:Acetylation; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D017353:Gene Deletion; D020043:Genes, Essential; D056084:Genetic Fitness; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013696:Temperature
D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; C496551:Esa1 protein, S cerevisiae; D051548:Histone Acetyltransferases; C430718:SDS3 protein, S cerevisiae; D006655:Histone Deacetylases
DNA damage repair; ESA1/KAT5; HDACs; Rpd3L; Tip60