The Sir proteins of Saccharomyces cerevisiae: Mediators of transcriptional silencing and much more

Current Opinion in Microbiology

Volumn 3, Issue 2, 2000, Pages 132-137

  Gartenberg, Marc R ^a  

^a UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FUNGAL PROTEIN; RIBOSOME DNA; TRANSFER RNA;

CELL CYCLE; CHROMATIN STRUCTURE; DNA REPLICATION; FUNGAL GENETICS; GENE REPRESSION; GENETIC TRANSCRIPTION; NONHUMAN; REVIEW; SACCHAROMYCES CEREVISIAE; TRANSCRIPTION REGULATION; YEAST;

SACCHAROMYCES CEREVISIAE;

EID: 0034109318     PISSN: 13695274     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1369-5274(00)00064-3     Document Type: Review

References (61)

1. Stevenson J.B., Gottschling D.E. Telomeric chromatin modulates replication timing near chromosome ends. Genes Dev. 13:1999;146-151. This paper identified a role for silent chromatin in determining the late S phase replication of telomeric DNA. By measuring replication times directly and mapping replication fork movements, the authors showed that firing of one sub-telomeric replication origin was delayed by silent chromatin whereas the firing of another was eliminated altogether.
2. Loo S., Rine J. Silencing and heritable domains of gene expression. Ann Rev Cell Dev Biol. 11:1995;519-548.
3. Haber J.E. Mating-type gene switching in Saccharomyces cerevisiae. Annu Rev Genet. 32:1998;561-599.
4. Palladino F., Laroche T., Gilson E., Axelrod A., Pillus L., Gasser S.M. SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres. Cell. 75:1993;543-555.
5. Lustig A.J. Mechanisms of silencing in Saccharomyces cerevisiae. Curr Opin Genet Dev. 8:1998;233-239.
6. Tse C., Sera T., Wolffe A.P., Hansen J.C. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol Cell Biol. 18:1998;4629-4638.
7. Ansari A., Gartenberg M.R. Persistence of an alternate chromatin structure at silenced loci in vitro. Proc Natl Acad Sci USA. 96:1999;343-348.
8. Sherman J.M., Stone E.M., Freeman-Cook L.L., Brachmann C.B., Boeke J.D., Pillus L. The conserved core of a human SIR2 homologue functions in yeast silencing. Mol Biol Cell. 10:1999;3045-3059.
9. Baker Brachmann C., Sherman J.M., Devine S.E., Cameron E.E., Pillus L., Boeke J.D. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9:1995;2888-2902.
10. Braustein M., Rose A.B., Holmes S.G., Allis C.D., Broach J.R. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7:1993;592-604.
11. 32P]NAD to bovine serum albumin. CobB was also able to transfer the ADP-ribosyl moiety from NAD to dimethylbenzimidazole. Although further work is required to fully understand these reactions, the preliminary findings may represent a major milestone.
12. Xie J., Pierce M., Gailus-Durner V., Wagner M., Winter E., Vershon A.K. Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae. EMBO J. 18:1999;6448-6454. These authors showed that one of the four S. cerevisiae SIR2 homologs, HST1, also functions directly in transcriptional repression. HST1 prevented the expression of middle sporulation specific genes in mitotic cells. The Hst1 protein was tethered to the promoters of these genes by Sum1, another protein that has long been implicated in silencing.
13. Chen X.J., Clark-Walker G.D. sir2 mutants of Kluyveromyces lactis are hypersensitive to DNA-targeting drugs. Mol Cell Biol. 14:1994;4501-4508.
14. Freeman-Cook L.L., Sherman J.M., Brachmann C.B., Allshire R.C., Boeke J.D., Pillus L. The Schizosaccharomyces pombe hst4+ gene is a SIR2 homologue with silencing and centromeric functions. Mol Biol Cell. 10:1999;3171-3186. The hst4+ gene from the distantly related fission yeast Schizosaccharomyces pombe was shown to be a SIR2 homologue. hst4+ contributed to silencing of telomere and centromere-proximal genes, and appeared to participate in chromosome segregation. The gene also complemented hst3 and hst4 silencing defects in S. cerevisiae.
15. Tsang A.W., Escalante-Semerena J.C. 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 in Salmonella typhimurium LT2. J Biol Chem. 273:1998;31788-31794.
16. Zemzoumi K., Sereno D., Francois C., Guilvard E., Lemesre J.L., Ouaissi A. Leishmania major: cell type dependent distribution of a 43 kDa antigen related to silent information regulatory-2 protein family. Biol Cell. 90:1998;239-245.
17. Triolo T., Sternglanz R. Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Nature. 381:1996;251-253.
18. Gardner K.A., Rine J., Fox C.A. A region of Sir1 protein dedicated to recognition of a silencer and required for interaction with the Orc1 protein in Saccharomyces cerevisiae. Genetics. 151:1999;31-44.
19. Bi X., Broach J.R. DNA in transcriptionally silent chromatin assumes a distinct topology that is sensitive to cell cycle progression. Mol Cell Biol. 17:1997;7077-7087.
20. Cheng T-H., Li Y-C., Gartenberg M.R. Persistence of an alternate chromatin structure at silenced loci in the absence of silencers. Proc Natl Acad Sci USA. 95:1998;5521-5526.
21. •]).
22. Pryde F.E., Louis E.J. Limitations of silencing at native telomeres. EMBO J. 18:1999;2538-2550. Expression levels of reporter genes targeted throughout subtelomeric regions showed that TPE was discontinuous at native telomeres. The existence of boundary elements was inferred. ORC and Abf1 sites within some of the repeated sequence elements were shown to contribute to TPE.
23. Boscheron C., Maillet L., Marcand S., Tsai-Pflugfelder M., Gasser S.M., Gilson E. Cooperation at a distance between silencers and proto-silencers at the yeast HML locus. EMBO J. 15:1996;2184-2195.
24. Bi X., Braunstein M., Shei G.J., Broach J.R. The yeast HML I silencer defines a heterochromatin domain boundary by directional establishment of silencing. Proc Natl Acad Sci USA. 96:1999;11934-11939. A detailed investigation of the silencing domain encompassing HML showed that repression was limited to the region flanked by silencers. No boundary elements were found at the locus. Inversion of one of the silencers, HML I, decreased silencing within the domain and strengthened silencing outside it, indicating that the silencer acts in a directional manner.
25. Wyrick J.J., Holstege F.C.P., Jennings E.G., Causton H.C., Shore D., Grunstein M., Lander E.S., Young R.A. Chromosomal landscape of nucleosome-dependent gene expression and silencing in yeast. Nature. 402:1999;418-421. Whole genome micro-arrays were used to study the influence of histone H4 depletion and SIR gene deletion on transcription. Elimination of SIR genes had a major effect on ORFs within 6-8 kb of telomeres. A number of other ORFs were also influenced but much of this can be attributed to indirect effects caused by derepression of the silent mating loci. Remarkably, depletion of H4 led to derepression of ORFs within regions spanning 20 kb from telomeres, well beyond the limits of Sir-mediated repression, suggesting that a Sir-independent mechanism may extend silent telomeric domains.
26. Donze D., Adams C.R., Rine J., Kamakaka R.T. The boundaries of the silenced HMR domain in Saccharomyces cerevisiae. Genes Dev. 13:1999;698-708. Boundary elements were found to flank the silenced domain encompassing HMR. Deletion of the boundary elements led to expansion of the silenced regions. When transferred to other silenced domains, the elements retained their function. The Smc proteins, which are involved in critical aspects of chromosome architecture, were required for boundary element function, though it is not clear whether this was a direct effect.
27. rpg, which contains three tandem Rap1 binding sites.
28. Cockell M., Gasser S.M. Nuclear compartments and gene regulation. Curr Opin Genet Dev. 9:1999;199-205.
29. Renauld H., Aparicio O.M., Zierath P.D., Billington B.L., Chhablani S.K., Gottschling D.E. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage. Genes Dev. 7:1993;1133-1145.
30. Hecht A., Strahl-Bolsinger S., Grunstein M. Spreading of transcriptional repressor Sir3 from telomeric heterochromatin. Nature. 383:1996;92-95.
31. Marcand S., Buck S.W., Moretti P., Gilson E., Shore D. Silencing of genes at nontelomeric sites in yeast is controlled by sequestration of silencing factors at telomeres by Rap1 protein. Genes Dev. 10:1996;1297-1309.
32. Maillet L., Boscheron C., Gotta M., Marcand S., Gilson E., Gasser S.M. Evidence of silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Genes Dev. 10:1996;1796-1811.
33. Lustig A.J., Liu C., Zhang C., Hanish J.P. Tethered Sir3p nucleates silencing at telomeres and internal loci in Saccharomyces cerevisiae. Mol Cell Biol. 16:1996;2483-2495.
34. Smith J.S., Brachmann C.B., Pillus L., Boeke J.D. Distribution of a limited Sir2 protein pool regulates the strength of yeast rDNA silencing and is modulated by Sir4p. Genetics. 149:1998;1205-1219.
35. Martin S.G., Laroche T., Suka N., Grunstein M., Gasser S.M. Relocalization of telomeric Ku and Sir proteins in response to DNA strand breaks in yeast. Cell. 97:1999;621-633. This paper documented the dynamic redistribution of Sir proteins and Ku upon DNA damage. Cytological and chromatin immunoprecipitation data showed that a single genomic double-strand break triggered release of Ku and Sir proteins from telomeres, allowing the proteins to redistribute to the damage site. The involvement of a DNA damage checkpoint in the process indicated that transfer was not dictated by mass action. Redistribution of the proteins also caused loss of TPE while improving silencing at internal sites.
36. Andrulis E., Neiman A.M., Zappulla D.C., Sternglanz R. Perinuclear localization of chromatin facilitates transcriptional silencing. Nature. 394:1998;592-595.
37. Haber J.E. Sir-Ku-itous routes to make ends meet. Cell. 97:1999;829-832.
38. Boulton S.J., Jackson S.P. Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J. 17:1998;1819-1828.
39. Gravel S., Larrivee M., Labrecque P., Wellinger R.J. Yeast Ku as a regulator of chromosomal DNA end structure. Science. 280:1998;741-744.
40. Laroche T., Martin S.G., Gotta M., Gorham H.C., Pryde F.E., Louis E.J., Gasser S.M. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr Biol. 8:1998;653-656.
41. Tsukamoto Y., Kato J-I., Ikeda H. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature. 388:1997;900-903.
42. Mishra K., Shore D. Yeast Ku protein plays a direct role in telomeric silencing and counteracts inhibition by Rif proteins. Curr Biol. 9:1999;1123-1126.
43. ••], the authors demonstrated that the sensitivity was not due entirely to derepression of the silent mating type loci.
44. ••].
45. •], the authors found that loss of NHEJ in sir mutants was due primarily (but not completely) to derepression of a and α gene expression at the silent mating loci. The authors also showed that simultaneous expression of the a and α genes resulted in measurable increases in the efficiency of repair by homologous recombination.
46. Gottlieb S., Esposito R.E. A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell. 56:1989;771-776.
47. Fritze C.E., Verschueren K., Strich R., Easton Esposito R. Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA. EMBO J. 16:1997;6495-6509.
48. Gotta M., Strahl-Bolsinger S., Renauld H., Laroche T., Kennedy B.K., Grunstein M., Gasser S.M. Localization of Sir2p: the nucleolus as a compartment for silent information regulators. EMBO J. 16:1997;3243-3255.
49. Smith J.S., Boeke J.D. An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 11:1997;241-254.
50. Bryk M., Banerjee M., Murphy M., Knudson K.E., Garfinkel D.J., Curcio M.J. Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev. 11:1997;255-269.
51. Straight A.F., Shou W., Dowd G.J., Turck C.W., Deshaies R.J., Johnson A.D., Moazed D. Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell. 97:1999;245-256. Protein affinity chromatography was used to isolate Net1 as a Sir2 interacting factor. Chromatin immunoprecipitation experiments showed that Net1 associated with rDNA. Deletion of NET1 eliminated association of Sir2 with rDNA and abolished rDNA silencing. Net1 was also shown to maintain the nucleolar localization of other proteins, Cdc14 and Nop1.
52. Shou W., Seol J.H., Shevchenko A., Basskerville C., Moazed D., Chen W.S., Jang J., Shevchenko A., Charbonneau H., Deshaies R.J. Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell. 97:1999;233-244. In this paper, NET1 was isolated in a genetic screen for bypass suppressors of a mitotic exit defect. Immunoaffinity chromatography with Net1 isolated the components of RENT, which included the mitotic regulator Cdc14, as well as Sir2 and Nan1. Cytological data demonstrated that Cdc14 was released from the nucleolus in late anaphase. Net1 was shown to be an inhibitor and target of the Cdc14 phosphatase activity. In this paper and in [53], the authors conjectured that nucleolar sequestration may be a general mechanism for regulating the activities of proteins that function elsewhere in the cell.
53. Visintin R., Hwang E.S., Amon A. Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. Nature. 398:1999;818-823.
54. San-Segundo P.A., Roeder G.S. Pch2 links chromatin silencing to meiotic checkpoint control. Cell. 97:1999;313-324. PCH2 was isolated in a genetic screen for mediators of meiotic checkpoints. In pch2 mutants, meiotic progression proceeds despite defects in chromosome synapsis and recombination, resulting in chromosome missegregation and low spore viability. Immunofluorescence showed that localization of Pch2 to the nucleolus required Sir2. Deletion of the SIR2 gene also abolished the meiotic checkpoint. Marker loss assays showed that both proteins were required to prevent meiotic recombination of the rDNA.
55. Sinclair D., Mills K., Guarente L. Aging in Saccharomyces cerevisiae. Annu Rev Microbiol. 52:1998;533-560.
56. Sinclair D.A., Guarente L. Extrachromosomal rDNA circles: a cause of aging in yeast. Cell. 7:1997;1033-1042.
57. 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. 13:1999;2570-2580. Pedigree analysis, rDNA recombination assays, and direct examination of rDNA structure was used to investigate relationships between the SIR genes, aging, and recombination events that form ERCs. The influence of SIR genes on aging was found to be independent of the NHEJ pathway. SIR2 was shown to have a direct role by suppressing homologous recombination induced by Fob1-mediated replication blocks in the rDNA [58]. SIR3 and SIR4, as part of the SIR2/3/4 complex, were shown to contribute indirectly by repressing a and α gene expression at the silent mating-type loci. Deletion of SIR4 in diploids, which naturally express both a and α genes, or in haploids that lacked silent loci had no effect on life span. The paper is particularly valuable because it prompts reevaluation of earlier data that suggested more direct roles for SIR3 and SIR4 [55].
58. Defossez P-A., Prusty R., Kaeberlein M., Lin S-J., Ferrigno P., Silver P.A., Keil R.L., Guarente L. Elimination of replication block protein Fob1 extends the lifespan of yeast mother cells. Mol Cell. 3:1999;447-455.
59. Imai S-i., Armstrong C.M., Kaeberlein M., Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 403:2000;795-800.
60. Tanny J.C., Dowd G.J., Huang J., Hilz H., Moazed D. An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell. 99:1999;735-745.
61. Cheng T-H., Gartenberg M.R. Maintenance of yeast heterochromatin is a dynamic process that requires silencers continuously. Genes Dev. 14:2000;452-463.