Mutations in Saccharomyces Cerevisiae Gene SIR2 Can Have Differential Effects on in Vivo Silencing Phenotypes and in Vitro Histone Deacetylation Activity

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2002 Apr 16

PMID 11950950

Citations 24

Authors

Christopher M Armstrong

Matt Kaeberlein

Shin Ichiro Imai

Leonard Guarente

Affiliations

Soon will be listed here.

Abstract

The yeast SIR2 gene and many of its homologs have been identified as NAD(+)-dependent histone deacetylases. To get a broader view of the relationship between the histone deacetylase activity of Sir2p and its in vivo functions we have mutated eight highly conserved residues in the core domain of SIR2. These mutations have a range of effects on the ability of Sir2p to deacetylate histones in vitro and to silence genes at the telomeres and HM loci. Interestingly, there is not a direct correlation between the in vitro and in vivo effects in some of these mutations. We also show that the histone deacetylase activity of Sir2p is necessary for the proper localiztion of the SIR complex to the telomeres.

Citing Articles

Novel interactions within the silent information regulator heterochromatin complex potentiate inter-subunit communication and gene repression.

Kotz J, Martz E, Nelson M, Savoie N, Schmitt L, States J bioRxiv. 2025; .

PMID: 39763739 PMC: 11703230. DOI: 10.1101/2024.12.23.630195.

Dual activities of a silencing information regulator complex in yeast transcriptional regulation and DNA-damage response.

Rybchuk J, Xiao W mLife. 2024; 3(2):207-218.

PMID: 38948145 PMC: 11211678. DOI: 10.1002/mlf2.12108.

Sir2 and Reb1 antagonistically regulate nucleosome occupancy in subtelomeric X-elements and repress TERRAs by distinct mechanisms.

Bauer S, Grochalski T, Smialowska A, Astrom S PLoS Genet. 2022; 18(9):e1010419.

PMID: 36137093 PMC: 9531808. DOI: 10.1371/journal.pgen.1010419.

Acetylation-dependent regulation of BRAF oncogenic function.

Dai X, Zhang X, Yin Q, Hu J, Guo J, Gao Y Cell Rep. 2022; 38(3):110250.

PMID: 35045286 PMC: 8813213. DOI: 10.1016/j.celrep.2021.110250.

Biophysical characterization of hit compounds for mechanism-based enzyme activation.

Guan X, Upadhyay A, Munshi S, Chakrabarti R PLoS One. 2018; 13(3):e0194175.

PMID: 29547630 PMC: 5856274. DOI: 10.1371/journal.pone.0194175.

References

Kayne P, Kim U, Han M, Mullen J, Yoshizaki F, Grunstein M . Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast. Cell. 1988; 55(1):27-39. DOI: 10.1016/0092-8674(88)90006-2. View

Wu J, Grunstein M . 25 years after the nucleosome model: chromatin modifications. Trends Biochem Sci. 2000; 25(12):619-23. DOI: 10.1016/s0968-0004(00)01718-7. View

Park E, Szostak J . Point mutations in the yeast histone H4 gene prevent silencing of the silent mating type locus HML. Mol Cell Biol. 1990; 10(9):4932-4. PMC: 361112. DOI: 10.1128/mcb.10.9.4932-4934.1990. View

Frye R . Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999; 260(1):273-9. DOI: 10.1006/bbrc.1999.0897. View

Imai S, ARMSTRONG C, Kaeberlein M, Guarente L . Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000; 403(6771):795-800. DOI: 10.1038/35001622. View

Straight A, Shou W, Dowd G, Turck C, Deshaies R, Johnson A . Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell. 1999; 97(2):245-56. DOI: 10.1016/s0092-8674(00)80734-5. View

Kaeberlein M, McVey M, Guarente L . The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999; 13(19):2570-80. PMC: 317077. DOI: 10.1101/gad.13.19.2570. View

Tsang A, Escalante-Semerena J . CobB, a new member of the SIR2 family of eucaryotic regulatory proteins, is required to compensate for the lack of nicotinate mononucleotide:5,6-dimethylbenzimidazole phosphoribosyltransferase activity in cobT mutants during cobalamin biosynthesis.... J Biol Chem. 1998; 273(48):31788-94. DOI: 10.1074/jbc.273.48.31788. View

Shou W, Seol J, Baskerville C, Moazed D, Chen Z, Jang J . Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell. 1999; 97(2):233-44. DOI: 10.1016/s0092-8674(00)80733-3. View

10.

Tanny J, Moazed D . Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NAD breakdown product. Proc Natl Acad Sci U S A. 2001; 98(2):415-20. PMC: 14600. DOI: 10.1073/pnas.98.2.415. View

11.

Smith J, Boeke J . An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 1997; 11(2):241-54. DOI: 10.1101/gad.11.2.241. View

12.

Tsukamoto Y, Kato J, Ikeda H . Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature. 1997; 388(6645):900-3. DOI: 10.1038/42288. View

13.

Smith J, Brachmann C, Celic I, Kenna M, Muhammad S, Starai V . A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc Natl Acad Sci U S A. 2000; 97(12):6658-63. PMC: 18692. DOI: 10.1073/pnas.97.12.6658. View

14.

Min J, Landry J, Sternglanz R, Xu R . Crystal structure of a SIR2 homolog-NAD complex. Cell. 2001; 105(2):269-79. DOI: 10.1016/s0092-8674(01)00317-8. View

15.

Gottlieb S, Esposito R . A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell. 1989; 56(5):771-6. DOI: 10.1016/0092-8674(89)90681-8. View

16.

Sutton A, Heller R, Landry J, Choy J, Sirko A, Sternglanz R . A novel form of transcriptional silencing by Sum1-1 requires Hst1 and the origin recognition complex. Mol Cell Biol. 2001; 21(10):3514-22. PMC: 100273. DOI: 10.1128/MCB.21.10.3514-3522.2001. View

17.

Tanny J, Dowd G, Huang J, Hilz H, Moazed D . An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell. 2000; 99(7):735-45. DOI: 10.1016/s0092-8674(00)81671-2. View

18.

Landry J, Slama J, Sternglanz R . Role of NAD(+) in the deacetylase activity of the SIR2-like proteins. Biochem Biophys Res Commun. 2000; 278(3):685-90. DOI: 10.1006/bbrc.2000.3854. View

19.

Braunstein M, Rose A, Holmes S, Allis C, Broach J . Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 1993; 7(4):592-604. DOI: 10.1101/gad.7.4.592. View

20.

Lin S, Defossez P, Guarente L . Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000; 289(5487):2126-8. DOI: 10.1126/science.289.5487.2126. View