Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss

Scott G. Holmes, Alan B. Rose, Kristin Steuerle, Enrique Saez, Sandra Sayegh, Young Mi Lee, James Broach

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The SIR gene products maintain transcriptional repression at the silent mating type loci and telomeres in Saccharomyces cerevisiae, although no enzymatic or structural activity has been assigned to any of the Sir proteins nor has the role of any of these proteins in transcriptional silencing been clearly defined. We have investigated the functions and interactions of the Sir2, Sir3, and Sir4 proteins by overexpressing them in yeast cells. We find that Sir2p and Sir3p are toxic when overexpressed, while high Sir4p levels have no toxic effect. Epistasis experiments indicate that Sir2p-induced toxicity is diminished in strains lacking the SIR3 gene, while both Sir2p and Sir4p are required for Sir3p to manifest its full toxic effect. In addition, the effects of Sir2 or Sir3 overexpression are exacerbated by specific mutations in the N-terminus of the histone H4 gene. These results are consistent with a model in which Sir2p, Sir3p and Sir4p function as a complex and interact with histones to modify chromatin structure. We find no evidence that toxicity from high levels of the Sir proteins results from widespread repression of transcription. Instead, we find that high levels of Sir2p and/or Sir3p cause a profound decrease in chromosome stability. These results can be appreciated in the context of the effects of Sir2p in histone acetylation and of chromatin structure on chromosome stability.

Original languageEnglish (US)
Pages (from-to)605-614
Number of pages10
JournalGenetics
Volume145
Issue number3
StatePublished - Mar 1 1997

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Poisons
Chromosomes
Histones
Chromosomal Instability
Chromatin
Proteins
Genes
Telomere
Acetylation
Saccharomyces cerevisiae
Yeasts
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Holmes, S. G., Rose, A. B., Steuerle, K., Saez, E., Sayegh, S., Lee, Y. M., & Broach, J. (1997). Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss. Genetics, 145(3), 605-614.
Holmes, Scott G. ; Rose, Alan B. ; Steuerle, Kristin ; Saez, Enrique ; Sayegh, Sandra ; Lee, Young Mi ; Broach, James. / Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss. In: Genetics. 1997 ; Vol. 145, No. 3. pp. 605-614.
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Holmes, SG, Rose, AB, Steuerle, K, Saez, E, Sayegh, S, Lee, YM & Broach, J 1997, 'Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss', Genetics, vol. 145, no. 3, pp. 605-614.

Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss. / Holmes, Scott G.; Rose, Alan B.; Steuerle, Kristin; Saez, Enrique; Sayegh, Sandra; Lee, Young Mi; Broach, James.

In: Genetics, Vol. 145, No. 3, 01.03.1997, p. 605-614.

Research output: Contribution to journalArticle

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T1 - Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss

AU - Holmes, Scott G.

AU - Rose, Alan B.

AU - Steuerle, Kristin

AU - Saez, Enrique

AU - Sayegh, Sandra

AU - Lee, Young Mi

AU - Broach, James

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N2 - The SIR gene products maintain transcriptional repression at the silent mating type loci and telomeres in Saccharomyces cerevisiae, although no enzymatic or structural activity has been assigned to any of the Sir proteins nor has the role of any of these proteins in transcriptional silencing been clearly defined. We have investigated the functions and interactions of the Sir2, Sir3, and Sir4 proteins by overexpressing them in yeast cells. We find that Sir2p and Sir3p are toxic when overexpressed, while high Sir4p levels have no toxic effect. Epistasis experiments indicate that Sir2p-induced toxicity is diminished in strains lacking the SIR3 gene, while both Sir2p and Sir4p are required for Sir3p to manifest its full toxic effect. In addition, the effects of Sir2 or Sir3 overexpression are exacerbated by specific mutations in the N-terminus of the histone H4 gene. These results are consistent with a model in which Sir2p, Sir3p and Sir4p function as a complex and interact with histones to modify chromatin structure. We find no evidence that toxicity from high levels of the Sir proteins results from widespread repression of transcription. Instead, we find that high levels of Sir2p and/or Sir3p cause a profound decrease in chromosome stability. These results can be appreciated in the context of the effects of Sir2p in histone acetylation and of chromatin structure on chromosome stability.

AB - The SIR gene products maintain transcriptional repression at the silent mating type loci and telomeres in Saccharomyces cerevisiae, although no enzymatic or structural activity has been assigned to any of the Sir proteins nor has the role of any of these proteins in transcriptional silencing been clearly defined. We have investigated the functions and interactions of the Sir2, Sir3, and Sir4 proteins by overexpressing them in yeast cells. We find that Sir2p and Sir3p are toxic when overexpressed, while high Sir4p levels have no toxic effect. Epistasis experiments indicate that Sir2p-induced toxicity is diminished in strains lacking the SIR3 gene, while both Sir2p and Sir4p are required for Sir3p to manifest its full toxic effect. In addition, the effects of Sir2 or Sir3 overexpression are exacerbated by specific mutations in the N-terminus of the histone H4 gene. These results are consistent with a model in which Sir2p, Sir3p and Sir4p function as a complex and interact with histones to modify chromatin structure. We find no evidence that toxicity from high levels of the Sir proteins results from widespread repression of transcription. Instead, we find that high levels of Sir2p and/or Sir3p cause a profound decrease in chromosome stability. These results can be appreciated in the context of the effects of Sir2p in histone acetylation and of chromatin structure on chromosome stability.

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Holmes SG, Rose AB, Steuerle K, Saez E, Sayegh S, Lee YM et al. Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss. Genetics. 1997 Mar 1;145(3):605-614.