Sir2

Sir2 (whose homolog in mammals is known as SIRT1, SIR2L1 or Sir2α) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied.[1] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.[2][3]

Nomenclature in various organisms

The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.[4] The term sirtuin is derived from Sir2 and stands for Silent Information Regulator Two (Sir2) protein.[5]

The name Sir2 is used for the enzyme in the yeast Saccharomyces cerevisiae (where it was first discovered), in the fruit fly Drosophila melanogaster, while in the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[6][7]

The various sirtuins in mammals are referred to as SIRT1-SIRT7 with SIRT1 being the mammalian ortholog closest in structure and function to Sir2.[1][8]

Method of action and observed effects

Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1.[9] They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose.

Sir2 is the only Class III histone deacetylase (HDAC) in budding yeast.'[10] The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed.

Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,[10] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.[10] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.[11] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.[11]

Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.[12] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[13] support these findings. As of 2006, experiments in mice are underway.[2]

However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan [14] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[15]

In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.

Resveratrol is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress.[2] Although there is mounting evidence for this hypothesis, its validity is debated.[16][17][18][19]

In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the p53 protein.[20] SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation), proteins required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.[21] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[22][23][24][25][26][27]

In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[12] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[28]

Mammal sirtuins

Seven sirtuins are known in mammals.

References

  1. 1 2 Frye, R (2000). "Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins". Biochemical and Biophysical Research Communications 273 (2): 793–8. doi:10.1006/bbrc.2000.3000. PMID 10873683.
  2. 1 2 3 Sinclair, David A.; Guarente, Lenny (2006). "Unlocking the Secrets of Longevity Genes". Scientific American 294 (3): 48–51, 54–7. doi:10.1038/scientificamerican0306-48. PMID 16502611.
  3. ↑ Noriega, Lilia G.; Feige, Jérôme N.; Canto, Carles; Yamamoto, Hiroyasu; Yu, Jiujiu; Herman, Mark A.; Mataki, Chikage; Kahn, Barbara B.; Auwerx, Johan (2011-10-01). "CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability". EMBO reports 12 (10): 1069–1076. doi:10.1038/embor.2011.151. ISSN 1469-3178. PMC 3185337. PMID 21836635.
  4. ↑ Rine, Jasper; Herskowitz, Ira (May 1987). "Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae". Genetics 116 (1): 9–22. PMC 1203125. PMID 3297920.
  5. ↑ North, Brian J; Verdin, Eric (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases.". Genome Biology 5 (5): 224. doi:10.1186/gb-2004-5-5-224. PMC 416462. PMID 15128440.
  6. ↑ WormBase Protein Summary: Sir-2.1
  7. ↑ http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239 Skyscape Content: Do antiaging approaches promote longevity?
  8. ↑ Dryden, S. C.; Nahhas, F. A.; Nowak, J. E.; Goustin, A.-S.; Tainsky, M. A. (2003). "Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle". Molecular and Cellular Biology 23 (9): 3173–85. doi:10.1128/MCB.23.9.3173-3185.2003. PMC 153197. PMID 12697818.
  9. ↑ The Sir2 protein family from EMBL's InterPro database
  10. 1 2 3 Chang, K; Min, KT (2002). "Regulation of lifespan by histone deacetylase". Ageing Research Reviews 1 (3): 313–26. doi:10.1016/S1568-1637(02)00003-X. PMID 12067588.
  11. 1 2 Kaeberlein, M.; McVey, M.; Guarente, L. (1999). "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms". Genes & Development 13 (19): 2570–80. doi:10.1101/gad.13.19.2570. PMC 317077. PMID 10521401.
  12. 1 2 EntrezGene 34708 Drosophilia Sir2
  13. ↑ Rogina, B.; Helfand, SL (2004). "Sir2 mediates longevity in the fly through a pathway related to calorie restriction". Proceedings of the National Academy of Sciences 101 (45): 15998–6003. doi:10.1073/pnas.0404184101. PMC 528752. PMID 15520384.
  14. ↑ Fabrizio, Paola; Gattazzo, Cristina; Battistella, Luisa; Wei, Min; Cheng, Chao; McGrew, Kristen; Longo, Valter D. (2005). "Sir2 Blocks Extreme Life-Span Extension". Cell 123 (4): 655–67. doi:10.1016/j.cell.2005.08.042. PMID 16286010.
  15. ↑ Kaeberlein, Matt; Kirkland, Kathryn T.; Fields, Stanley; Kennedy, Brian K. (2004). "Sir2-Independent Life Span Extension by Calorie Restriction in Yeast". PLoS Biology 2 (9): e296. doi:10.1371/journal.pbio.0020296. PMC 514491. PMID 15328540.
  16. ↑ Kaeberlein, M.; McDonagh, T; Heltweg, B; Hixon, J; Westman, EA; Caldwell, SD; Napper, A; Curtis, R; et al. (2005). "Substrate-specific Activation of Sirtuins by Resveratrol". Journal of Biological Chemistry 280 (17): 17038–45. doi:10.1074/jbc.M500655200. PMID 15684413.
  17. ↑ Borra, M. T.; Smith, BC; Denu, JM (2005). "Mechanism of Human SIRT1 Activation by Resveratrol". Journal of Biological Chemistry 280 (17): 17187–95. doi:10.1074/jbc.M501250200. PMID 15749705.
  18. ↑ Pacholec, M.; Bleasdale, J. E.; Chrunyk, B.; Cunningham, D.; Flynn, D.; Garofalo, R. S.; Griffith, D.; Griffor, M.; et al. (2010). "SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1". Journal of Biological Chemistry 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378.
  19. ↑ Beher, Dirk; Wu, John; Cumine, Suzanne; Kim, Ki Won; Lu, Shu-Chen; Atangan, Larissa; Wang, Minghan (2009). "Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity". Chemical Biology & Drug Design 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076.
  20. ↑ EntrezGene 23411 Human Sirt1
  21. ↑ Lee, I. H.; Cao, L.; Mostoslavsky, R.; Lombard, D. B.; Liu, J.; Bruns, N. E.; Tsokos, M.; Alt, F. W.; Finkel, T. (2008). "A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy". Proceedings of the National Academy of Sciences 105 (9): 3374–9. doi:10.1073/pnas.0712145105.
  22. ↑ Wilson, B. J.; Tremblay, A. M.; Deblois, G.; Sylvain-Drolet, G.; Giguere, V. (2010). "An Acetylation Switch Modulates the Transcriptional Activity of Estrogen-Related Receptor". Molecular Endocrinology 24 (7): 1349–58. doi:10.1210/me.2009-0441. PMID 20484414.
  23. ↑ Rodgers, Joseph T.; Lerin, Carlos; Haas, Wilhelm; Gygi, Steven P.; Spiegelman, Bruce M.; Puigserver, Pere (2005). "Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1". Nature 434 (7029): 113–8. doi:10.1038/nature03354. PMID 15744310.
  24. ↑ Nemoto, S.; Fergusson, MM; Finkel, T (2005). "SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1". Journal of Biological Chemistry 280 (16): 16456–60. doi:10.1074/jbc.M501485200. PMID 15716268.
  25. ↑ Lagouge, Marie; Argmann, Carmen; Gerhart-Hines, Zachary; Meziane, Hamid; Lerin, Carles; Daussin, Frederic; Messadeq, Nadia; Milne, Jill; et al. (2006). "Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α". Cell 127 (6): 1109–22. doi:10.1016/j.cell.2006.11.013. PMID 17112576.
  26. ↑ Liu, Yi; Dentin, Renaud; Chen, Danica; Hedrick, Susan; Ravnskjaer, Kim; Schenk, Simon; Milne, Jill; Meyers, David J.; et al. (2008). "A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange". Nature 456 (7219): 269–73. doi:10.1038/nature07349. PMC 2597669. PMID 18849969.
  27. ↑ Cantó, Carles; Gerhart-Hines, Zachary; Feige, Jerome N.; Lagouge, Marie; Noriega, Lilia; Milne, Jill C.; Elliott, Peter J.; Puigserver, Pere; Auwerx, Johan (2009). "AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity". Nature 458 (7241): 1056–60. doi:10.1038/nature07813. PMC 3616311. PMID 19262508.
  28. ↑ McBurney, M. W.; Yang, X.; Jardine, K.; Hixon, M.; Boekelheide, K.; Webb, J. R.; Lansdorp, P. M.; Lemieux, M. (2003). "The Mammalian SIR2 Protein Has a Role in Embryogenesis and Gametogenesis". Molecular and Cellular Biology 23 (1): 38–54. doi:10.1128/MCB.23.1.38-54.2003. PMC 140671. PMID 12482959.
  29. ↑ Ford, E.; Voit, R; Liszt, G; Magin, C; Grummt, I; Guarente, L (2006). "Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription". Genes & Development 20 (9): 1075–80. doi:10.1101/gad.1399706. PMC 1472467. PMID 16618798.

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