Histone deacetylase
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Histone deacetylases (HDAC) (EC number 3.5.1) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferase.
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[edit] Subtypes
HDAC proteins are found in three groups, the first two groups belong to the classical HDACs and their activities are inhibited by trichostatin A (TSA) whereas the third group is a family of NAD+-dependent proteins not affected by TSA. Homologues to all three groups are found in yeast having the names reduced potassium dependency 3 (Rpd3) - corresponds to class 1, histone deacetylase 1 (hda1) – to class 2 and silent information regulator 2(Sir2) – class3.[1]
[edit] Subcellular distribution
Within the class I HDACs, HDAC 1, 2 and 8 are primarily found in the nucleus, whereas HDAC 3 is found both in the nucleus, cytoplasm and also membrane associated. Class II HDACs (HDAC 4, 5, 6, 7 9 and 10) are able to shuttle in and out of the nucelus depending on different signals.[2][3]
HDAC 6 is a cytoplasmic, microtuble-associated enzyme. HDAC 6 deacetylates tubulin, Hsp90 and cortactin, and forms complexes with other partner proteins and is therefore involved in a variety of biological processes.[4]
[edit] Function
Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.
Histone deacetylase is involved in a series of pathways within the living system. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), these are:
- Environmental information processing; signal transduction; notch signaling pathway PATH:ko04330
- Cellular processes; cell growth and death; cell cycle PATH:ko04110
- Human diseases; cancers; chronic myeloid leukemia PATH:ko05220
Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.[5] Their study also found a regulatory crosstalk between HDAC1 and HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,[6] negatively correlating with the expression of GAD67 mRNA.
It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogus mechanism, in which non-histone proteins are acted on by acetylases and deacetylases [7]. It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are transcription factors and co-regulators, some are not. Note the following four examples:
- HDAC6 is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.[8]
- PTEN is an important phosphatase involved in cell signaling via phosphoinositols and the AKT/PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (PCAF) can stimulate its activity; conversely, deacetylation of PTEN by SIRT1 deacetylase and apparently by HDAC1 can repress its activity.[9][10]
- APE1/Ref-1 (APEX) is a multifunctional protein possessing both DNA repair activity (on abasic and single strand break sites) and transcriptional regulatory activity associated with oxidative stress. APE1/Ref-1 is acetylated by PCAF; conversely it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its DNA repair activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormone gene.[11][12]
- NF-kB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via HDAC3 and HDAC6.[13]
These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
[edit] HDAC inhibitors
Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epilectics, for example, valproic acid. More recently, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.[14][15] Also in recent years, there has been an effort to develop HDIs for cancer therapy, and Vorinostat (SAHA) has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[16] In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.[17]
HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and thereby increase or repress their activity. For the four examples given above (see Function) on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1.[18][19]
[edit] Family
Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.[20] Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily.IPR000286
[edit] Classes of HDACs in higher eukaryotes
HDACs, are classified in four classes depending on sequence identity and domain organization:[21]
- Class I
- Class II
- Class III
- Class IV
[edit] See also
- Histone deacetylase inhibitor
- Histone methyltransferase
- Histone-modifying enzymes
- RNA polymerase control by chromatin structure
[edit] References
- ^ Sengupta N, Seto E (September 2004). "Regulation of histone deacetylase activities". J. Cell. Biochem. 93 (1): 57–67. doi:. PMID 15352162.
- ^ de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (March 2003). "Histone deacetylases (HDACs): characterization of the classical HDAC family". Biochem. J. 370 (Pt 3): 737–49. doi:. PMID 12429021.
- ^ Longworth MS, Laimins LA (July 2006). "Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src". Oncogene 25 (32): 4495–500. doi:. PMID 16532030.
- ^ Valenzuela-Fernández A, Cabrero JR, Serrador JM, Sánchez-Madrid F (June 2008). "HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions". Trends Cell Biol. 18 (6): 291–7. doi:. PMID 18472263.
- ^ Zupkovitz G, Tischler J, Posch M, et al. (2006). "Negative and positive regulation of gene expression by mouse histone deacetylase 1". Mol. Cell. Biol. 26 (21): 7913–28. doi:. PMID 16940178.
- ^ Sharma RP, Grayson DR, Gavin DP (2007). "Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray collection". Schizophrenia Research 98: 111. doi:. PMID 17961987.
- ^ Glozak MA, Sengupta N, Zhang X, Seto E (2005). "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23. doi:. PMID 16289629.
- ^ Rodriguez-Gonzalez A, Lin T, Ikeda AK, Simms-Waldrip T, Fu C, Sakamoto KM (2008). "Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation". Cancer Res. 68 (8): 2557–60. doi:. PMID 18413721.
- ^ Ikenoue T, Inoki K, Zhao B, Guan KL (2008). "PTEN acetylation modulates its interaction with PDZ domain". Cancer Res. 68 (17): 6908–12. doi:. PMID 18757404.
- ^ Yao XH, Nyomba BL (2008). "Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring". Am J Physiol Regul Integr Comp Physiol 294 (6): R1797–806. PMID 18385463.
- ^ Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S (2003). "Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene". Embo J. 22 (23): 6299–309. doi:. PMID 14633989.
- ^ Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G (2008). "APE1/Ref-1 regulates PTEN expression mediated by Egr-1". Free Radic Res. 42 (1): 20–9. doi:. PMID 18324520.
- ^ Hasselgren PO (2007). "Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting". J Cell Physiol. 213 (3): 679–89. doi:. PMID 17657723.
- ^ Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (February 2008). "Histone deacetylase inhibitors: possible implications for neurodegenerative disorders". Expert Opin Investig Drugs 17 (2): 169–84. doi:. PMID 18230051.
- ^ "Scientists 'reverse' memory loss". BBC News. http://news.bbc.co.uk/2/hi/health/6606315.stm. Retrieved on 2007-07-08.
- ^ Monneret C (2007). "Histone deacetylase inhibitors for epigenetic therapy of cancer". Anticancer Drugs 18 (4): 363–70. doi:. PMID 17351388.
- ^ Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov
- ^ Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005). "Clinical development of histone deacetylase inhibitors as anticancer agents". Annu Rev Pharmacol Toxicol 45: 495–528. doi:. PMID 15822187.
- ^ Yang XJ, Seto E (2007). "HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention". Oncogene 26: 5310–5318. doi:. PMID 17694074.
- ^ Leipe DD, Landsman D (1997). "Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily". Nucleic Acids Res. 25 (18): 3693–7. doi:. PMID 9278492.
- ^ Dokmanovic M, Clarke C, Marks PA (2007). "Histone deacetylase inhibitors: overview and perspectives". Mol. Cancer Res. 5 (10): 981–9. doi:. PMID 17951399.
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