I am a student at the University of Western Ontario taking part in the 3595 Ad Gen Wikipedia Project. I am intending to improve the article Daf-16, and this sandbox contains my draft.

A crystalline structure of the protein FOXO, encoded by Daf-16

Evaluating Articles

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TATA box

The article is pretty focused on the topic, there is not much unnecessary distracting information - although on the talk page there are comments that information about histones are unnecessary because only people who have been educated in biology would be familiar with the term.

There is a citation needed in the first paragraph, where it says the core DNA sequence is normally followed by 3 or more adenine bases [1]

It describes the scientific process using the words 'normally' and 'usually' - is this correct?

The second to last paragraph does not include the name of the study even though it is referenced

It is a stub rated, high class importance article and a project on WikiProject Genetics

Possible articles to edit

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genetic viability wild type - grammar needs fixed chromosomal deletion syndrome. could add definition of a deletion = loss of parts of chromosomes, generally visible on karyotyping because they are larger deletions definition of karyotyping = looking at the appearance of chromosomes

My article to edit

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Daf-16 I will add: the gene is daf 16 - FOXO transcription factor it 65% is similar to the protein FOXO in humans - homologous to four FOXOs http://www.sciencedirect.com/science/article/pii/S0531556515300498 FOXO 3 increases lifespan

its structure located downstream of IIS kinase cascade https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361755/

its function needed for longevity - activates proteins involved in stress resistance and longevity such as MnSOD, CuZnSOD, catalase,heat shock proteins, chaperones, stress response proteins is also involved in regulating epidermis damage https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798571/

clinical relevance this gene can be targeted in ageing studies

Daf 16 draft

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DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[2] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[3] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[4] Daf -16 is responsible for the protection of C. elegans during food deprivation [5], causing it to transform into a hibernation - like state, known as a Dauer.

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[6] It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses.[7][8] It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. [9] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[10] The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism. [11]

DAF-16
 
A crystalline structure of the protein FOXO, encoded by Daf-16
Gene DAF-16
Protein FOXO
Location Chromosome 1
Position 175-268
Organism Caenorhabditis elegans

Genetics

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DAF-16 is a gene conserved across species, with homologs being found in C. elegans, humans, mice, and Drosophila (fruit flies).[12] In C. elegans, DAF-16 is located on Chromosome 1, at position 175-268. [13] It is made up of 15 exons. [14] DAF-16 is also located downstream of Daf-2, which signals in the IIS pathway. Mutants in this pathway age slower and have a lifespan up to twice as long as normal. [15] The lifespan extension is dependent on DAF-16. [16] Other consequences of mutations in the Daf-16 gene is the inability to form dauers. [17]

FOXO (Forkhead box protein O)

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DAF-16 encodes FOXO (Forkhead box protein O), which binds to gene promoters that contain the sequence TTGTTTAC in their regulatory region – this is the DAF-16 binding element (DBE). [18] FOXO is involved in the Insulin / IGF1 signalling pathway (IIS) which affects longevity, lipogenesis, dauer formation, heat shock and oxidative stress responses, by activating proteins such as MnSOD and Catalase. [19] Expression of FOXO in the intestine normally leads to longevity signalling. [20] It is inhibited by the protein AKT in the IIS pathway, as DAF-16 is inactivated when phosphorylated[21], which is why a reduction in insulin signalling generally leads to longevity in C. elegans and across species. FOXO has been shown to have a protective role against cancer, as it regulates and suppresses genes involved in tumour formation. [22] It also has a protective role against muscular dystrophy. [23]

FOXO is also important in embryonic development, as it promotes apoptosis. [24]

For the carbon dioxide avoidance response, inhibition of Daf-16 is needed. [25] When inhibition is lost, Daf-16 translocates to the nucleus and regulates genes that delay growth and reproduction but increase stress resistance and longevity[26]

File:IGF signalling pathway

Daf-16 mutants fail to arrest cell division in L1 arrest as it is dependent for transcription of the cyclin-dependent kinase inhibitor cki-1 in response to starvation in stem cells. [27]


Insulin Signalling Insulin is the primary hormone dictating energy functions such as glucose and lipid metabolism. The signalling pathway is evolutionary conserved and found across species. Insulin activates an insulin receptor molecule (in C. elegans, this is DAF-2), which in turn activates a kinase and AKT. However AKT inhibits DAF-16 and FOXO, so a reduction in insulin signalling corresponds to an increase in FOXO and the longevity proteins it activates.

Insulin and IGF1 are peptide hormones dictating energy functions such as glucose and lipid metabolism. [28] The signalling pathway is evolutionary conserved and found across species.[29] Signalling occurs through kinases such as PI3K to produce phospholipid products such as AKT. [30]This causes downstream phosphorylation of targets such as DAF-16 by a phosphorylation cascade, blocking nuclear entry. Therefore a reduction in insulin signalling generally leads to an increase in FOXO expression. [31]When not phosphorylated, DAF-16 is active and present in the nucleus, [32] so FOXO can be transcribed and can up-regulate production of about 100 beneficial proteins that increase longevity. [33]

Species, tissue, subcellular distribution

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C. elegans is the only known species to contain the DAF-16 gene[34] , although orthologs are conserved across species[35]. DAF-16 may localise to the nucleus or cytoplasm, depending on resources.[36] In nutrient rich conditions, Daf-2 and Akt-1/Akt-2 in the insulin pathway inhibits entry of DAF-16 to the nucleus as it is phosphorylated. However starvation, heat and oxidative stress inhibit phosphorylation by AKT and allow the localisation of DAF-16 to the nucleus. [37]DAF-16 is sequestered in the cytoplasm when associated with ftt-2.[38] Translocation to the nucleus and translation of longevity genes occurs after DAF-16 associates with prmpt-1 [39] Translocation to the nucleus is also promoted by jnk-1 in heat stress and sek-1 in oxidative stress [40] [41]

Expression

Isoform b and Isoform c are expressed in muscles, ectoderm, the intestine and neurones.[42] Isoform b is additionally expressed in the pharynx.[43] Expression can be induced by quinic acid.[44]

Clinical Significance

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Implication in Aging

DAF-16 is necessary for dauer formation and the protection of C. elegans during periods of starvation, as DAF-16, DAF-18 and DAF-12 loss - of - function mutants lose the ability to form dauers. [45] A 2003 study by Murphy et. al showed the significance of DAF-16 for longevity, as it up-regulates genes involved in lifespan extension such as stress response genes and down regulates specific life-shortening genes. [46] It has been proven that telomeres have an implication in the aging process, and in C. elegans the lifespan - extending effect of long telomeres is dependent on DAF-16. [47] DAF-2 mutations more than double the lifespan of C. elegans, and this effect is dependent on the activity of DAF-16 as it encodes a member of the hepatocyte nuclear family 3 (HNF3)/ Forkhead family of transcription factors.[48]

C. elegans has long been used in aging research. [49] Although DAF-16 increases longevity, treating C.elegans with resvatrol extends lifespan in a method independent of Daf-16 and fully dependent on SIR2.1. [50]

Interactions

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Daf-16 is known to interact with:

History

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In 1963 Sydney Brenner realised the success of biology was due to model organisms, and C. elegans has been widely used in research laboratories since.[57] In 1998 the genome of C. elegans was completely sequenced and found to be a 97 megabase genomic sequence consisting of 19,000 genes, with 40% protein products having significant matches in other organisms. [58] The DAF genes DAF-2 and DAF-16 were discovered in the Thomas and Ruvkun labs, after isolating dauer-consituative (DAF-c) mutants and dauer - defective mutants (DAF-d). Mutations in Daf-2 and DAF-23 caused the dauer - constitutive phenotype, through activation of the dauer - defective genes DAF-16 and DAF-18[59]. This showed that DAF-2 and DAF-23 prevent dauer arrest by antagonising DAF-16 and DAF-18 [60]

Notable scientists involved in the initial and continued characterization of DAF-16-associated aging pathways:

See also

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A crystalline structure of the protein FOXO, encoded by Daf-16

| Protein = [[FOX proteins | FOXO]

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References

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  1. ^ Cann, Alan. Principles of Molecular Virology (Standard ed.).
  2. ^ daf-16 at WormBase www.wormbase.org
  3. ^ Ogg, S; Paradis, S; Gottlieb, S; Patterson, GI; Lee, L; Tissenbaum, HA; Ruvkun, G (Oct 30, 1997). "The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans". Nature. 389 (6654): 994–9. doi:10.1038/40194. PMID 9353126.
  4. ^ Kenyon, C. (29 November 2010). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philosophical Transactions of the Royal Society B: Biological Sciences. 366 (1561): 9–16. doi:10.1098/rstb.2010.0276. PMC 3001308. PMID 21115525.
  5. ^ Henderson, ST. "daf-16 protects the nematode Caenorhabditis elegans during food deprivation".
  6. ^ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science (New York, N.Y.). pp. 1319–1322.
  7. ^ Henderson, S. T.; Johnson, T. E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current biology: CB. pp. 1975–1980.
  8. ^ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science (New York, N.Y.). pp. 1319–1322.
  9. ^ Fielenbach, Nicole; Antebi, Adam (15 August 2008). "C. elegans dauer formation and the molecular basis of plasticity". Genes & Development. pp. 2149–2165. doi:10.1101/gad.1701508.
  10. ^ Ogg, S; Paradis, S; Gottlieb, S; Patterson, GI; Lee, L; Tissenbaum, HA; Ruvkun, G (Oct 30, 1997). "The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans". Nature. 389 (6654): 994–9. doi:10.1038/40194. PMID 9353126.
  11. ^ Kenyon, C. (29 November 2010). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philosophical Transactions of the Royal Society B: Biological Sciences. 366 (1561): 9–16. doi:10.1098/rstb.2010.0276. PMC 3001308. PMID 21115525.
  12. ^ Hesp, Kylie; Smant, Geert; Kammenga, Jan E. (NaN). "Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease". Experimental Gerontology. pp. 1–7. doi:10.1016/j.exger.2015.09.006. {{cite web}}: Check date values in: |date= (help)
  13. ^ "blastp results [running]". www.uniprot.org.
  14. ^ "daf-16 Forkhead box protein O [Caenorhabditis elegans] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  15. ^ Lin, K.; Hsin, H.; Libina, N.; Kenyon, C. (NaN). "Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling". Nature Genetics. pp. 139–145. doi:10.1038/88850. {{cite web}}: Check date values in: |date= (help)
  16. ^ Lin, K.; Hsin, H.; Libina, N.; Kenyon, C. (NaN). "Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling". Nature Genetics. pp. 139–145. doi:10.1038/88850. {{cite web}}: Check date values in: |date= (help)
  17. ^ Gottlieb, S.; Ruvkun, G. (NaN). "Daf-2, Daf-16 and Daf-23: Genetically Interacting Genes Controlling Dauer Formation in Caenorhabditis Elegans". Genetics. pp. 107–120. {{cite web}}: Check date values in: |date= (help)
  18. ^ "Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues".
  19. ^ Lin, Kui. "daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans".
  20. ^ Libina, Nataliya. "Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan".
  21. ^ Yen, Kelvin. "DAF-16/Forkhead Box O Transcription Factor: Many Paths to a Single Fork(head) in the Road".
  22. ^ Pinkston-Gosse, Julie; Kenyon, Cynthia (NaN). "DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans". Nature Genetics. pp. 1403–1409. doi:10.1038/ng.2007.1. {{cite web}}: Check date values in: |date= (help)
  23. ^ Catoire, Hélène; Pasco, Matthieu Y.; Abu-Baker, Aida; Holbert, Sébastien; Tourette, Cendrine; Brais, Bernard; Rouleau, Guy A.; Parker, J. Alex; Néri, Christian (15 July 2008). "Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1". Human Molecular Genetics. pp. 2108–2117. doi:10.1093/hmg/ddn109.
  24. ^ Nakagawa, Akihisa; Sullivan, Kelly D.; Xue, Ding (NaN). "Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway". Nature Structural & Molecular Biology. pp. 1082–1090. doi:10.1038/nsmb.2915. {{cite web}}: Check date values in: |date= (help)
  25. ^ Bretscher, Andrew Jonathan; Busch, Karl Emanuel; de Bono, Mario (10 June 2008). "A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans". Proceedings of the National Academy of Sciences of the United States of America. pp. 8044–8049. doi:10.1073/pnas.0707607105.
  26. ^ Henderson, S. T.; Johnson, T. E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current biology: CB. pp. 1975–1980.
  27. ^ Baugh, L. Ryan; Sternberg, Paul W. (18 April 2006). "DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest". Current biology: CB. pp. 780–785. doi:10.1016/j.cub.2006.03.021.
  28. ^ Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald (NaN). "Insulin Receptor Signaling in Normal and Insulin-Resistant States". Cold Spring Harbor Perspectives in Biology. doi:10.1101/cshperspect.a009191. {{cite web}}: Check date values in: |date= (help)
  29. ^ Barbieri, Michelangela; Bonafè, Massimiliano; Franceschi, Claudio; Paolisso, Giuseppe (NaN). "Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans". American Journal of Physiology. Endocrinology and Metabolism. pp. E1064–1071. doi:10.1152/ajpendo.00296.2003. {{cite web}}: Check date values in: |date= (help)
  30. ^ Gami, Minaxi S; Wolkow, Catherine A (NaN). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell. pp. 31–37. doi:10.1111/j.1474-9726.2006.00188.x. {{cite web}}: Check date values in: |date= (help)
  31. ^ O'Neill, Brian T.; Lee, Kevin Y.; Klaus, Katherine; Softic, Samir; Krumpoch, Megan T.; Fentz, Joachim; Stanford, Kristin I.; Robinson, Matthew M.; Cai, Weikang; Kleinridders, Andre; Pereira, Renata O.; Hirshman, Michael F.; Abel, E. Dale; Accili, Domenico; Goodyear, Laurie J.; Nair, K. Sreekumaran; Kahn, C. Ronald (1 September 2016). "Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis". The Journal of Clinical Investigation. pp. 3433–3446. doi:10.1172/JCI86522.
  32. ^ Henderson, S. T.; Johnson, T. E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current biology: CB. pp. 1975–1980.
  33. ^ Greer, Eric L; Brunet, Anne (14 November 2005). "FOXO transcription factors at the interface between longevity and tumor suppression". Oncogene. pp. 7410–7425. doi:10.1038/sj.onc.1209086.
  34. ^ Hesp, Kylie. "Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease".
  35. ^ Lee, RY. "Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway".
  36. ^ "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans".
  37. ^ Henderson, Samuel T.; Johnson, Thomas E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current Biology. pp. 1975–1980. doi:10.1016/S0960-9822(01)00594-2.
  38. ^ Takahashi, Y. "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism.
  39. ^ Takahashi, Y. "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism.
  40. ^ Kondo, Masaki; Yanase, Sumino; Ishii, Takamasa; Hartman, Philip S.; Matsumoto, Kunihiro; Ishii, Naoaki (NaN). "The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei". Mechanisms of Ageing and Development. pp. 642–647. doi:10.1016/j.mad.2004.11.012. {{cite web}}: Check date values in: |date= (help)
  41. ^ Oh, Seung Wook; Mukhopadhyay, Arnab; Svrzikapa, Nenad; Jiang, Feng; Davis, Roger J.; Tissenbaum, Heidi A. (22 March 2005). "JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16". Proceedings of the National Academy of Sciences of the United States of America. pp. 4494–4499. doi:10.1073/pnas.0500749102.
  42. ^ Wolf, Marc; Nunes, Frank; Henkel, Arne; Heinick, Alexander; Paul, Rüdiger J. (NaN). "The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation, and influences over temperature-dependent insulin-like signaling, stress responses, and fitness". Journal of Cellular Physiology. pp. 721–729. doi:10.1002/jcp.21269. {{cite web}}: Check date values in: |date= (help)
  43. ^ Lee, R. Y.; Hench, J.; Ruvkun, G. (11 December 2001). "Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway". Current biology: CB. pp. 1950–1957.
  44. ^ Zhang, Longze; Zhang, Junjing; Zhao, Baolu; Zhao-Wilson, Xi (NaN). "Quinic acid could be a potential rejuvenating natural compound by improving survival of Caenorhabditis elegans under deleterious conditions". Rejuvenation Research. pp. 573–583. doi:10.1089/rej.2012.1342. {{cite web}}: Check date values in: |date= (help)
  45. ^ Cypser, James R.; Johnson, Thomas E. (2003). "Hormesis in Caenorhabditis elegans dauer-defective mutants". Biogerontology. pp. 203–214.
  46. ^ Murphy, Coleen. "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans | Learn Science at Scitable". www.nature.com.
  47. ^ Joeng, Kyu Sang; Song, Eun Joo; Lee, Kong-Joo; Lee, Junho (NaN). "Long lifespan in worms with long telomeric DNA". Nature Genetics. pp. 607–611. doi:10.1038/ng1356. {{cite web}}: Check date values in: |date= (help)
  48. ^ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science (New York, N.Y.). pp. 1319–1322.
  49. ^ Tissenbaum, Heidi A. (30 January 2015). "Using C. elegans for aging research". Invertebrate Reproduction & Development. pp. 59–63. doi:10.1080/07924259.2014.940470.
  50. ^ Viswanathan, Mohan; Kim, Stuart K.; Berdichevsky, Ala; Guarente, Leonard (NaN). "A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span". Developmental Cell. pp. 605–615. doi:10.1016/j.devcel.2005.09.017. {{cite web}}: Check date values in: |date= (help)
  51. ^ Li, Wensheng; Gao, Beixue; Lee, Sang-Myeong; Bennett, Karen; Fang, Deyu (NaN). "RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination". Developmental Cell. pp. 235–246. doi:10.1016/j.devcel.2006.12.002. {{cite web}}: Check date values in: |date= (help)
  52. ^ Takahashi, Yuta; Daitoku, Hiroaki; Hirota, Keiko; Tamiya, Hiroko; Yokoyama, Atsuko; Kako, Koichiro; Nagashima, Yusuke; Nakamura, Ayumi; Shimada, Takashi; Watanabe, Satoshi; Yamagata, Kazuyuki; Yasuda, Kayo; Ishii, Naoaki; Fukamizu, Akiyoshi (4 May 2011). "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism. pp. 505–516. doi:10.1016/j.cmet.2011.03.017.
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Category:Caenorhabditis elegans genes Category:Aging-related proteins


Notes

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[1]

  1. ^ [1] TATA box is followed by the base adenine