Landry J, Sutton A, Tafrov S T, Heller R C, Stebbins J, Pillus L, Sternglanz R
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794-5215, USA.
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11. doi: 10.1073/pnas.110148297.
Homologs of the chromatin-bound yeast silent information regulator 2 (SIR2) protein are found in organisms from all biological kingdoms. SIR2 itself was originally discovered to influence mating-type control in haploid cells by locus-specific transcriptional silencing. Since then, SIR2 and its homologs have been suggested to play additional roles in suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging. Considering the far-ranging nature of these functions, a major experimental goal has been to understand the molecular mechanism(s) by which this family of proteins acts. We report here that members of the SIR2 family catalyze an NAD-nicotinamide exchange reaction that requires the presence of acetylated lysines such as those found in the N termini of histones. Significantly, these enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases. The enzymes are active on histone substrates that have been acetylated by both chromatin assembly-linked and transcription-related acetyltransferases. Contrary to a recent report, we find no evidence that these proteins ADP-ribosylate histones. Discovery of an intrinsic deacetylation activity for the conserved SIR2 family provides a mechanism for modifying histones and other proteins to regulate transcription and diverse biological processes.
染色质结合型酵母沉默信息调节因子2（SIR2）蛋白的同源物存在于所有生物界的生物体中。SIR2本身最初是通过位点特异性转录沉默来影响单倍体细胞中的交配型控制而被发现的。从那时起，SIR2及其同源物被认为在抑制重组、染色体稳定性、代谢调节、减数分裂和衰老中发挥额外作用。考虑到这些功能的广泛性质，一个主要的实验目标是了解该蛋白家族发挥作用的分子机制。我们在此报告，SIR2家族成员催化一种NAD-烟酰胺交换反应，该反应需要存在乙酰化赖氨酸，如在组蛋白N末端发现的那些。重要的是，这些酶还在绝对需要NAD的反应中催化组蛋白去乙酰化，从而将它们与先前表征的去乙酰化酶区分开来。这些酶对已被染色质组装相关和转录相关乙酰转移酶乙酰化的组蛋白底物具有活性。与最近的一份报告相反，我们没有发现这些蛋白对组蛋白进行ADP-核糖基化的证据。保守的SIR2家族内在去乙酰化活性的发现为修饰组蛋白和其他蛋白质以调节转录和多种生物过程提供了一种机制。
