Gene Silencing Protein Found to Be Enzyme Modifier

Researchers have found that the Sir2 protein, known to be required for gene silencing, modifies the enzyme acetyl-CoA synthetase that may be related to the extended lifespan in many organisms resulting when calories are restricted. The finding was reported in the December 20, 2002, issue of Science.

Silencing is a form of transcriptional repression that renders large chromatin domains inaccessible to the transcription machinery. Silenced domains are refractile to recombination, replicate late in S phase and are inaccessible to some but not all molecular probes. In Saccharomyces cerevisiae (budding yeast) silencing occurs at three loci: the cryptic mating type loci, HMR and HML; the telomeres (referred as telomeric position effect, TPE); and at the rDNA locus (called RPE).

SIR2 distinguishes itself from the other SIR genes as it is essential for the three types of silencing and is conserved from bacteria to man. Four paralogs of Sir2p exist in budding yeast, the Hst1-4 proteins, and more than one Sir2 ortholog is found in all other species examined. They are called sirtuins. Recently, numerous studies have demonstrated that Sir2p is an in vitro NAD-dependent deacetylase and that this enzymatic activity appears to correlate with repression at the HM, telomeres, and rDNA loci. However, the physiologic Sir2p substrates have not yet been identified.

Working with a mutated strain of bacteria lacking sirtuins, investigators from Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) and the University of Wisconsin (Madison, USA; www.wisc.edu) discovered that Sir2 was a crucial modifier of the enzyme acetyl-CoA synthetase, which converts acetate into acetyl-CoA in a two-step process. Acetyl-CoA then can directly fuel the citric acid cycle, the central energy-producing step in cellular respiration.

"This is a completely new target for the sirtuin protein,” explained investigator Dr. Jeff Boeke, professor of molecular biology and genetics at Johns Hopkins' Institute for Basic Biomedical Sciences. "Converting acetate is not the cell's only way of making acetyl-CoA, but when acetate is the major energy source, it is crucial. Now we have to check for this role in other organisms.”




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University of Wisconsin