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Sirtuin 1#Sir2

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-{{merge to|Sirtuin 1|date=October 2012}}
+#REDIRECT [[Sirtuin 1#Sir2]]
-'''Sir2''' (whose [[homology (biology)|homolog]] in [[mammal]]s 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 [[Conservation (genetics)|highly conserved]] family have been found in nearly all organisms studied.<ref name="Pp">{{cite journal |last1=Frye |first1=R |title=Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins |journal=Biochemical and Biophysical Research Communications |volume=273 |issue=2 |pages=793–8 |year=2000 |pmid=10873683 |doi=10.1006/bbrc.2000.3000}}</ref> 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]].<ref name=sinclair>{{cite journal |last1=Sinclair |first1=David A. |last2=Guarente |first2=Lenny |title=Unlocking the Secrets of Longevity Genes |journal=Scientific American |volume=294 |issue=3 |pages=48–51, 54–7 |year=2006 |pmid=16502611 |doi=10.1038/scientificamerican0306-48}}</ref><ref>{{Cite journal|title = CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability|url = http://www.ncbi.nlm.nih.gov/pubmed/21836635|journal = EMBO reports|date = 2011-10-01|issn = 1469-3178|pmc = 3185337|pmid = 21836635|pages = 1069-1076|volume = 12|issue = 10|doi = 10.1038/embor.2011.151|first = Lilia G.|last = Noriega|first2 = Jérôme N.|last2 = Feige|first3 = Carles|last3 = Canto|first4 = Hiroyasu|last4 = Yamamoto|first5 = Jiujiu|last5 = Yu|first6 = Mark A.|last6 = Herman|first7 = Chikage|last7 = Mataki|first8 = Barbara B.|last8 = Kahn|first9 = Johan|last9 = Auwerx}}</ref>
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-==Nomenclature in various organisms==
+{{R from merge}}
-The three letter yeast gene symbol ''Sir'' stands for <u>S</u>ilent <u>I</u>nformation <u>R</u>egulator while the number ''2'' is representative of the fact that it was the second SIR gene discovered and characterized.<ref>{{cite journal |last1=Rine |first1=Jasper |last2=Herskowitz |first2=Ira |title=Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae |journal=Genetics |volume=116 |issue=1 |pages=9–22 |date=May 1987 |pmid=3297920 |pmc=1203125 |url=http://www.genetics.org/cgi/pmidlookup?view=long&pmid=3297920}}</ref> The term sirtuin is derived from Sir2 and stands for ''<u>S</u>ilent <u>I</u>nformation <u>R</u>eg<u>u</u>lator <u>T</u>wo (Sir2) prote<u>in</u>''.<ref name="pmid15128440">{{cite journal |last1=North |first1=Brian J |last2=Verdin |first2=Eric |title=Sirtuins: Sir2-related NAD-dependent protein deacetylases. |journal=Genome Biology |volume=5 |issue=5 |pages=224 |year=2004 |pmid=15128440 |pmc=416462 |doi=10.1186/gb-2004-5-5-224}}</ref>
+{{R to section}}
+}}
-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.<ref>[http://wormbase.org/db/seq/protein?name=sir-2.1;class=Protein: WormBase Protein Summary: Sir-2.1]</ref><ref><nowiki>http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239</nowiki>{{Dead link|date=March 2011}} Skyscape Content: Do antiaging approaches promote longevity?</ref>
-The various sirtuins in mammals are referred to as SIRT1-SIRT7 with SIRT1 being the mammalian ortholog closest in structure and function to Sir2.<ref name="Pp" /><ref>{{cite journal |last1=Dryden |first1=S. C. |last2=Nahhas |first2=F. A. |last3=Nowak |first3=J. E. |last4=Goustin |first4=A.-S. |last5=Tainsky |first5=M. A. |title=Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle |journal=Molecular and Cellular Biology |volume=23 |issue=9 |pages=3173–85 |year=2003 |pmid=12697818 |pmc=153197 |doi=10.1128/MCB.23.9.3173-3185.2003}}</ref>
-==Method of action and observed effects==
-Sirtuins act primarily by removing [[acetyl]] groups from [[lysine]] residues within proteins in the presence of [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]]; thus, they are classified as "NAD<sup>+</sup>-dependent deacetylases" and have [[Enzyme Commission number|EC number]] 3.5.1.<ref>[http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003000 The Sir2 protein family] from [[EMBL]]'s InterPro database</ref> They add the acetyl group from the protein to the [[Adenosine diphosphate ribose|ADP-ribose]] component of NAD<sup>+</sup> to form O-acetyl-ADP-ribose.
-Sir2 is the only Class III [[histone deacetylase]] (HDAC) in budding yeast.'<ref name=pm12067588>{{cite journal |last1=Chang |first1=K |last2=Min |first2=KT |title=Regulation of lifespan by histone deacetylase |journal=Ageing Research Reviews |volume=1 |issue=3 |pages=313–26 |year=2002 |pmid=12067588 |doi=10.1016/S1568-1637(02)00003-X}}</ref> The HDAC activity of Sir2 results in tighter packaging of [[chromatin]] and a reduction in [[transcription (genetics)|transcription]] at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the [[Mating of yeast#HML and HMR: the silent mating cassettes|hidden MAT loci]] (HM loci), and the [[ribosome|ribosomal]] DNA (rDNA) locus (RDN1) from which [[ribosomal RNA]] is transcribed.
-Limited [[gene expression|overexpression]] of the Sir2 [[gene]] results in a lifespan extension of about 30%,<ref name="pm12067588"/> 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.<ref name=pm12067588 /> 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.<ref name=pm10521401>{{cite journal |last1=Kaeberlein |first1=M. |last2=McVey |first2=M. |last3=Guarente |first3=L. |title=The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms |journal=Genes & Development |volume=13 |issue=19 |pages=2570–80 |year=1999 |pmid=10521401 |pmc=317077 |doi=10.1101/gad.13.19.2570}}</ref> 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.<ref name=pm10521401 />
-Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD<sup>+</sup> 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.<ref name=Dros>{{EntrezGene|34708}} Drosophilia Sir2</ref> Experiments in the [[nematode]] ''[[Caenorhabditis elegans]]'' and in the fruit fly ''[[Drosophila melanogaster]]''<ref>{{cite journal |last1=Rogina |first1=B. |last2=Helfand |first2=SL |title=Sir2 mediates longevity in the fly through a pathway related to calorie restriction |journal=Proceedings of the National Academy of Sciences |volume=101 |issue=45 |pages=15998–6003 |year=2004 |pmid=15520384 |pmc=528752 |doi=10.1073/pnas.0404184101}}</ref> support these findings. {{As of|2006}}, experiments in [[Mus musculus|mice]] are underway.<ref name=sinclair/>
-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 <ref>{{cite journal |last1=Fabrizio |first1=Paola |last2=Gattazzo |first2=Cristina |last3=Battistella |first3=Luisa |last4=Wei |first4=Min |last5=Cheng |first5=Chao |last6=McGrew |first6=Kristen |last7=Longo |first7=Valter D. |title=Sir2 Blocks Extreme Life-Span Extension |journal=Cell |volume=123 |issue=4 |pages=655–67 |year=2005 |pmid=16286010 |doi=10.1016/j.cell.2005.08.042 }}</ref> Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.<ref>{{cite journal |last1=Kaeberlein |first1=Matt |last2=Kirkland |first2=Kathryn T. |last3=Fields |first3=Stanley |last4=Kennedy |first4=Brian K. |title=Sir2-Independent Life Span Extension by Calorie Restriction in Yeast |journal=PLoS Biology |volume=2 |issue=9 |pages=e296 |year=2004 |pmid=15328540 |pmc=514491 |doi=10.1371/journal.pbio.0020296}}</ref>
-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.<ref name=sinclair/> Although there is mounting evidence for this hypothesis, its validity is debated.<ref>{{cite journal |last1=Kaeberlein |first1=M. |last2=McDonagh |first2=T |last3=Heltweg |first3=B |last4=Hixon |first4=J |last5=Westman |first5=EA |last6=Caldwell |first6=SD |last7=Napper |first7=A |last8=Curtis |first8=R |last9=Distefano |first9=PS |last10=Fields |first10=S. |last11=Bedalov |first11=A. |last12=Kennedy |first12=B. K. |title=Substrate-specific Activation of Sirtuins by Resveratrol |journal=Journal of Biological Chemistry |volume=280 |issue=17 |pages=17038–45 |year=2005 |pmid=15684413 |doi=10.1074/jbc.M500655200|display-authors=8 }}</ref><ref>{{cite journal |last1=Borra |first1=M. T. |last2=Smith |first2=BC |last3=Denu |first3=JM |title=Mechanism of Human SIRT1 Activation by Resveratrol |journal=Journal of Biological Chemistry |volume=280 |issue=17 |pages=17187–95 |year=2005 |pmid=15749705 |doi=10.1074/jbc.M501250200}}</ref><ref name="pmid20061378">{{cite journal |last1=Pacholec |first1=M. |last2=Bleasdale |first2=J. E. |last3=Chrunyk |first3=B. |last4=Cunningham |first4=D. |last5=Flynn |first5=D. |last6=Garofalo |first6=R. S. |last7=Griffith |first7=D. |last8=Griffor |first8=M. |last9=Loulakis |first9=P. |last10=Pabst |first10=B. |last11=Qiu |first11=X. |last12=Stockman |first12=B. |last13=Thanabal |first13=V. |last14=Varghese |first14=A. |last15=Ward |first15=J. |last16=Withka |first16=J. |last17=Ahn |first17=K. |title=SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1 |journal=Journal of Biological Chemistry |volume=285 |issue=11 |pages=8340–51 |year=2010 |pmid=20061378 |pmc=2832984 |doi=10.1074/jbc.M109.088682|display-authors=8 }}</ref><ref>{{cite journal |last1=Beher |first1=Dirk |last2=Wu |first2=John |last3=Cumine |first3=Suzanne |last4=Kim |first4=Ki Won |last5=Lu |first5=Shu-Chen |last6=Atangan |first6=Larissa |last7=Wang |first7=Minghan |title=Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity |journal=Chemical Biology & Drug Design |volume=74 |issue=6 |pages=619–24 |year=2009 |pmid=19843076 |doi=10.1111/j.1747-0285.2009.00901.x}}</ref>
-In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the [[p53]] protein.<ref>{{EntrezGene|23411}} Human Sirt1</ref> 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.<ref>{{cite journal |last1=Lee |first1=I. H. |last2=Cao |first2=L. |last3=Mostoslavsky |first3=R. |last4=Lombard |first4=D. B. |last5=Liu |first5=J. |last6=Bruns |first6=N. E. |last7=Tsokos |first7=M. |last8=Alt |first8=F. W. |last9=Finkel |first9=T. |title=A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=9 |pages=3374–9 |year=2008 |doi=10.1073/pnas.0712145105 }}</ref> Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the [[PPARGC1A|PGC1-alpha]]/[[Estrogen-related receptor alpha|ERR-alpha]] complex, which are essential metabolic regulatory transcription factors.<ref name="pmid20484414">{{cite journal |last1=Wilson |first1=B. J. |last2=Tremblay |first2=A. M. |last3=Deblois |first3=G. |last4=Sylvain-Drolet |first4=G. |last5=Giguere |first5=V. |title=An Acetylation Switch Modulates the Transcriptional Activity of Estrogen-Related Receptor |journal=Molecular Endocrinology |volume=24 |issue=7 |pages=1349–58 |year=2010 |pmid=20484414 |doi=10.1210/me.2009-0441}}</ref><ref name="pmid15744310">{{cite journal |last1=Rodgers |first1=Joseph T. |last2=Lerin |first2=Carlos |last3=Haas |first3=Wilhelm |last4=Gygi |first4=Steven P. |last5=Spiegelman |first5=Bruce M. |last6=Puigserver |first6=Pere |title=Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1 |journal=Nature |volume=434 |issue=7029 |pages=113–8 |year=2005 |pmid=15744310 |doi=10.1038/nature03354}}</ref><ref name="pmid15716268">{{cite journal |last1=Nemoto |first1=S. |last2=Fergusson |first2=MM |last3=Finkel |first3=T |title=SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1  |journal=Journal of Biological Chemistry |volume=280 |issue=16 |pages=16456–60 |year=2005 |pmid=15716268 |doi=10.1074/jbc.M501485200}}</ref><ref name="pmid17112576">{{cite journal |last1=Lagouge |first1=Marie |last2=Argmann |first2=Carmen |last3=Gerhart-Hines |first3=Zachary |last4=Meziane |first4=Hamid |last5=Lerin |first5=Carles |last6=Daussin |first6=Frederic |last7=Messadeq |first7=Nadia |last8=Milne |first8=Jill |last9=Lambert |first9=Philip |last10=Elliott |first10=Peter |last11=Geny |first11=Bernard |last12=Laakso |first12=Markku |last13=Puigserver |first13=Pere |last14=Auwerx |first14=Johan |title=Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α |journal=Cell |volume=127 |issue=6 |pages=1109–22 |year=2006 |pmid=17112576 |doi=10.1016/j.cell.2006.11.013|display-authors=8 }}</ref><ref name="pmid18849969">{{cite journal |last1=Liu |first1=Yi |last2=Dentin |first2=Renaud |last3=Chen |first3=Danica |last4=Hedrick |first4=Susan |last5=Ravnskjaer |first5=Kim |last6=Schenk |first6=Simon |last7=Milne |first7=Jill |last8=Meyers |first8=David J. |last9=Cole |first9=Phil |last10=Iii |first10=John Yates |last11=Olefsky |first11=Jerrold |last12=Guarente |first12=Leonard |last13=Montminy |first13=Marc |title=A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange |journal=Nature |volume=456 |issue=7219 |pages=269–73 |year=2008 |pmid=18849969 |pmc=2597669 |doi=10.1038/nature07349|display-authors=8 }}</ref><ref name="pmid19262508">{{cite journal |last1=Cantó |first1=Carles |last2=Gerhart-Hines |first2=Zachary |last3=Feige |first3=Jerome N. |last4=Lagouge |first4=Marie |last5=Noriega |first5=Lilia |last6=Milne |first6=Jill C. |last7=Elliott |first7=Peter J. |last8=Puigserver |first8=Pere |last9=Auwerx |first9=Johan |title=AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity |journal=Nature |volume=458 |issue=7241 |pages=1056–60 |year=2009 |pmid=19262508 |doi=10.1038/nature07813 |pmc=3616311 }}</ref>
-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.<ref name=Dros/> However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.<ref>{{cite journal |last1=McBurney |first1=M. W. |last2=Yang |first2=X. |last3=Jardine |first3=K. |last4=Hixon |first4=M. |last5=Boekelheide |first5=K. |last6=Webb |first6=J. R. |last7=Lansdorp |first7=P. M. |last8=Lemieux |first8=M. |title=The Mammalian SIR2  Protein Has a Role in Embryogenesis and Gametogenesis |journal=Molecular and Cellular Biology |volume=23 |issue=1 |pages=38–54 |year=2003 |pmid=12482959 |pmc=140671 |doi=10.1128/MCB.23.1.38-54.2003}}</ref>
-==Mammal sirtuins==
-Seven sirtuins are known in mammals.
-* [[SIRT1]] (also known as Sir2α) is the mammal homolog of Sir2. Mice that overexpress SIRT1 show eight properties of calorie restriction, including low [[cholesterol]], low [[blood glucose]], and low [[insulin]] levels.  They also show increased numbers of [[mitochondria]] in their [[neuron]]s.
-* [[SIRT2]] is expressed mainly in the [[brain]].
-* [[SIRT3]], [[SIRT4]], and [[SIRT5]] are active in mitochondria, the energy-producing organelles that are a part of every cell.
-* [[SIRT6]] is active in the [[Cell nucleus|nucleus]] of the cell.
-* [[SIRT7]] is active in the [[nucleolus]], a compartment of the nucleus reserved for the assembly of [[ribosome]]s.  Sirt7 has been shown to activate [[RNA polymerase I]] transcription.<ref>{{cite journal |last1=Ford |first1=E. |last2=Voit |first2=R |last3=Liszt |first3=G |last4=Magin |first4=C |last5=Grummt |first5=I |last6=Guarente |first6=L |title=Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription |journal=Genes & Development |volume=20 |issue=9 |pages=1075–80 |year=2006 |pmid=16618798 |pmc=1472467 |doi=10.1101/gad.1399706}}</ref>
-==References==
-{{Reflist|2}}
-==External links==
-*{{EntrezGene|23411}} Human Sirt1
-*[http://genomics.senescence.info/genes/entry.php?hugo=SIRT1 Human Sirt1] in the GenAge database
-*[http://www.ihop-net.org/UniPub/iHOP/gismo/142188.html Sirt1] in the [[Information Hyperlinked over Proteins|iHOP]] database
-{{Carbon-nitrogen non-peptide hydrolases}}
-[[Category:Ageing]]
-[[Category:Aging-related genes]]
-[[Category:EC 3.5.1]]
-[[Category:Enzymes]]
-[[nl:Sirtuïne#Sir2]]