Sirtuin 1
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Location (UCSC) | Chr 10: 67.88 – 67.92 Mb | Chr 10: 63.15 – 63.22 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[5][6][7]
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).[8][9]
Function
Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. The protein encoded by this gene is included in class I of the sirtuin family.[6]
Sirtuin 1 is downregulated in cells that have high insulin resistance.[10] 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.[11][12]
In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein,[13] and may have a role in activating T helper 17 cells.[14]
Selective ligands
Activators
- Lamin A.[15] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.[21]
- SRT-1720 was also claimed to be an activator,[16] but this now has been questioned.[22]
- Methylene blue[23] by increasing NAD+/NADH ratio.
- Metformin activates both PRKA and SIRT1.[24]
Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK),[25] which increases NAD+ levels (which is the cofactor required for SIRT1 activity).[26][27] Elevating NAD+ is a more direct and reliable way to activate SIRT1.[27]
Interactions
Sirtuin 1 has been shown in vitro to
Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes.[29]
Sir2
Sir2 (whose
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.[33][34]
In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[35][36]
Method of action and observed effects
Sirtuins act primarily by removing
Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,[38] 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.[38] 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.[39] 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.[39]
Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces
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 [42] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[43]
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
In the fruit fly Drosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[40] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[44]
Inhibition of SIRT1
Human aging is characterized by a chronic, low-grade inflammation level,[45] and the pro-inflammatory transcription factor NF-κB is the main transcriptional regulator of genes related to inflammation.[46] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[47][48] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of the microRNA miR-34a (which inhibits nicotinamide adenine dinucleotide NAD+ synthesis) by binding to its promoter region.[49] resulting in lower levels of SIRT1.
Both the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation.[50] PARP1 is a DNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20-30% thereby reducing SIRT1 activity.[50]
Homologous recombination
SIRT1 protein actively promotes
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000096717 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020063 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 10381378.
- ^ a b "Entrez Gene: SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)".
- ^ SIRT1 human gene location in the UCSC Genome Browser.
- PMID 16502611.
- PMID 30416425.
- ^ PMID 17908559.
- ^ PMID 20484414.
- PMID 19262508.
- ^ EntrezGene 23411 Human Sirt1
- S2CID 27313960.
- ^ PMID 23217256.
- ^ S2CID 20849750.
- PMID 15684413.
- S2CID 205913187.
- PMID 23524286.
- PMID 23471411.
- S2CID 3991428.
- PMID 20061378.
- PMID 24486702.
- PMID 25484077.
- S2CID 85533334.
- PMID 31281594.
- ^ PMID 22106091.
- S2CID 205369422.
- PMID 22470339.
- PMID 10873683.
- ^ PMID 16502611.
- PMID 21836635.
- PMID 3297920.
- PMID 15128440.
- ^ WormBase Protein Summary: Sir-2.1
- ^ http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239 Archived 2007-09-27 at the Wayback Machine "Skyscape Content: Do antiaging approaches promote longevity?". Archived from the original on September 27, 2007. Retrieved July 6, 2016.
{{cite web}}
: CS1 maint: bot: original URL status unknown (link) Skyscape Content: Do antiaging approaches promote longevity? - EMBL's InterPro database
- ^ S2CID 39452909.
- ^ PMID 10521401.
- ^ a b EntrezGene 34708 Drosophila Sir2
- PMID 15520384.
- S2CID 1276690.
- PMID 15328540.
- PMID 12482959.
- PMID 24833586.
- PMID 20457564.
- PMID 15152190.
- PMID 23770291.
- PMID 32485811.
- ^ PMID 28664098.
- ^ PMID 20097625.
- PMID 12427531.
External links
- Corante weblog by Derek Lowe about sir2 and SIRT1 research.
- SIRT1 human gene location in the UCSC Genome Browser.
- SIRT1 human gene details in the UCSC Genome Browser.