Pathway: HDACs deacetylate histones
Reactions in pathway: HDACs deacetylate histones :
HDACs deacetylate histones
Lysine deacetylases (KDACs), historically referred to as histone deacetylases (HDACs), are divided into the Rpd3/Hda1 metal-dependent 'classical HDAC family' (de Ruijter et al. 2003, Verdin et al. 2003) and the unrelated sirtuins (Milne & Denu 2008). Phylogenetic analysis divides human KDACs into four classes (Gregoretti et al. 2004): Class I includes HDAC1, 2, 3 and 8; Class IIa includes HDAC4, 5, 7 and 9; Class IIb includes HDAC6 and 10; Class III are the sirtuins (SIRT1-7); Class IV has one member, HDAC11 (Gao et al. 2002). Class III enzymes use an NAD+ cofactor to perform deacetylation (Milne & Denu 2008, Yang & Seto 2008), the others classes use a metal-dependent mechanism (Gregoretti et al. 2004) to catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins yielding L-lysine and acetate. X-ray crystal structures are available for four human HDACs; these structures have conserved active site residues, suggesting a common catalytic mechanism (Lombardi et al. 2011). They require a single transition metal ion and are typically studied in vitro as Zn2+-containing enzymes, though in vivo HDAC8 exhibits increased activity when substituted with Fe2+ (Gantt et al. 2006). The structurally-related enzyme acetylpolyamine amidohydrolase (APAH) (Leipe & Landsman 1997) exhibits optimal activity with Mn2+, followed closely by Zn2+ (Sakurada et al. 1996).
HDACs are often part of multi-protein transcriptional complexes that are recruited to gene promoters, regulating transcription without direct DNA binding. With the exception of HDAC8, all class I members can be catalytic subunits of multiprotein complexes (Yang & Seto 2008). HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes (Grozinger & Schreiber 2002). HDAC3 is part of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR) (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011) which are involved in a wide range of processes including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013).
Class IIa HDACs (HDAC4, -5, -7, and -9) shuttle between the nucleus and cytoplasm (Yang & Seto 2008, Haberland et al. 2009). The nuclear export of class IIa HDACs requires phosphorylation stimulated by calcium or other stimuli. They appear to have been evolutionarily inactivated as enzymes, having acquired a histidine substitution of the tyrosine residue in the active site of the mammalian deacetylase domain (H976 in humans) (Lahm et al. 2007, Schuetz et al. 2008). Instead they function as transcriptional corepressors for the MEF2 family of transcription factors (Yang & Gregoire 2005) .
Histones are the primary substrate for most HDACs except HDAC6 which is predominantly cytoplasmic and acts on alpha-tublin (Hubbert et al. 2002, Zhang et al. 2003, Boyault et al. 2007). HDACs also deacetylate proteins such as p53, E2F1, RelA, YY1, TFIIE, BCL6 and TFIIF (Glozak et al. 2005).
Histone deacetylases are targeted by structurally diverse compounds known as HDAC inhibitors (HDIs) (Marks et al. 2000). These can induce cytodifferentiation, cell cycle arrest and apoptosis of transformed cells (Marks et al. 2000, Bolden et al. 2006). Some HDIs have significant antitumor activity (Marks and Breslow 2007, Ma et al. 2009) and at least two are approved anti-cancer drugs.
The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
HDACs are often part of multi-protein transcriptional complexes that are recruited to gene promoters, regulating transcription without direct DNA binding. With the exception of HDAC8, all class I members can be catalytic subunits of multiprotein complexes (Yang & Seto 2008). HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes (Grozinger & Schreiber 2002). HDAC3 is part of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR) (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011) which are involved in a wide range of processes including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013).
Class IIa HDACs (HDAC4, -5, -7, and -9) shuttle between the nucleus and cytoplasm (Yang & Seto 2008, Haberland et al. 2009). The nuclear export of class IIa HDACs requires phosphorylation stimulated by calcium or other stimuli. They appear to have been evolutionarily inactivated as enzymes, having acquired a histidine substitution of the tyrosine residue in the active site of the mammalian deacetylase domain (H976 in humans) (Lahm et al. 2007, Schuetz et al. 2008). Instead they function as transcriptional corepressors for the MEF2 family of transcription factors (Yang & Gregoire 2005) .
Histones are the primary substrate for most HDACs except HDAC6 which is predominantly cytoplasmic and acts on alpha-tublin (Hubbert et al. 2002, Zhang et al. 2003, Boyault et al. 2007). HDACs also deacetylate proteins such as p53, E2F1, RelA, YY1, TFIIE, BCL6 and TFIIF (Glozak et al. 2005).
Histone deacetylases are targeted by structurally diverse compounds known as HDAC inhibitors (HDIs) (Marks et al. 2000). These can induce cytodifferentiation, cell cycle arrest and apoptosis of transformed cells (Marks et al. 2000, Bolden et al. 2006). Some HDIs have significant antitumor activity (Marks and Breslow 2007, Ma et al. 2009) and at least two are approved anti-cancer drugs.
The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
Eukaryotic DNA is associated with histone proteins and organized into a complex nucleoprotein structure called chromatin. This structure decreases the accessibility of DNA but also helps to protect it from damage. Access to DNA is achieved by highly regulated local chromatin decondensation.
The 'building block' of chromatin is the nucleosome. This contains ~150 bp of DNA wrapped around a histone octamer which consists of two each of the core histones H2A, H2B, H3 and H4 in a 1.65 left-handed superhelical turn (Luger et al. 1997, Andrews & Luger 2011).
Most organisms have multiple genes encoding the major histone proteins. The replication-dependent genes for the five histone proteins are clustered together in the genome in all metazoans. Human replication-dependent histones occur in a large cluster on chromosome 6 termed HIST1, a smaller cluster HIST2 on chromosome 1q21, and a third small cluster HIST3 on chromosome 1q42 (Marzluff et al. 2002). Histone genes are named systematically according to their cluster and location within the cluster.
The 'major' histone genes are expressed primarily during the S phase of the cell cycle and code for the bulk of cellular histones. Histone variants are usually present as single-copy genes that are not restricted in their expression to S phase, contain introns and are often polyadenylated (Old & Woodland 1984). Some variants have significant differences in primary sequence and distinct biophysical characteristics that are thought to alter the properties of nucleosomes. Others localize to specific regions of the genome. Some variants can exchange with pre-existing major histones during development and differentiation, referred to as replacement histones (Kamakaka & Biggins 2005). These variants can become the predominant species in differentiated cells (Pina & Suau 1987, Wunsch et al. 1991). Histone variants may have specialized functions in regulating chromatin dynamics.
The H2A histone family has the highest sequence divergence and largest number of variants. H2A.Z and H2A.XH2A are considered 'universal variants', found in almost all organisms (Talbert & Henikoff 2010). Variants differ mostly in the C-terminus, including the docking domain, implicated in interactions with the (H3-H4)x2 tetramer within the nucleosome, and in the L1 loop, which is the interaction interface of H2A-H2B dimers (Bonisch & Hake 2012). Canonical H2A proteins are expressed almost exclusively during S-phase. There are several nearly identical variants (Marzluff et al. 2002). No functional specialization of these canonical H2A isoforms has been demonstrated (Bonisch & Hake 2012). Reversible histone modifications such as acetylation and methylation regulate transcription from genomic DNA, defining the 'readability' of genes in specific tissues (Kouzarides 2007, Marmorstein & Trievel 2009, Butler et al. 2012).
N.B. The coordinates of post-translational modifications represented here follow Reactome standardized naming, which includes the UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed; therefore the coordinates of post-translated histone residues described here are frequently +1 when compared with the literature. For more information on Reactome's standards for naming pathway events, the molecules that participate in them and representation of post-translational modifications, please refer to Naming Conventions on the Reactome Wiki or Jupe et al. 2014.
The 'building block' of chromatin is the nucleosome. This contains ~150 bp of DNA wrapped around a histone octamer which consists of two each of the core histones H2A, H2B, H3 and H4 in a 1.65 left-handed superhelical turn (Luger et al. 1997, Andrews & Luger 2011).
Most organisms have multiple genes encoding the major histone proteins. The replication-dependent genes for the five histone proteins are clustered together in the genome in all metazoans. Human replication-dependent histones occur in a large cluster on chromosome 6 termed HIST1, a smaller cluster HIST2 on chromosome 1q21, and a third small cluster HIST3 on chromosome 1q42 (Marzluff et al. 2002). Histone genes are named systematically according to their cluster and location within the cluster.
The 'major' histone genes are expressed primarily during the S phase of the cell cycle and code for the bulk of cellular histones. Histone variants are usually present as single-copy genes that are not restricted in their expression to S phase, contain introns and are often polyadenylated (Old & Woodland 1984). Some variants have significant differences in primary sequence and distinct biophysical characteristics that are thought to alter the properties of nucleosomes. Others localize to specific regions of the genome. Some variants can exchange with pre-existing major histones during development and differentiation, referred to as replacement histones (Kamakaka & Biggins 2005). These variants can become the predominant species in differentiated cells (Pina & Suau 1987, Wunsch et al. 1991). Histone variants may have specialized functions in regulating chromatin dynamics.
The H2A histone family has the highest sequence divergence and largest number of variants. H2A.Z and H2A.XH2A are considered 'universal variants', found in almost all organisms (Talbert & Henikoff 2010). Variants differ mostly in the C-terminus, including the docking domain, implicated in interactions with the (H3-H4)x2 tetramer within the nucleosome, and in the L1 loop, which is the interaction interface of H2A-H2B dimers (Bonisch & Hake 2012). Canonical H2A proteins are expressed almost exclusively during S-phase. There are several nearly identical variants (Marzluff et al. 2002). No functional specialization of these canonical H2A isoforms has been demonstrated (Bonisch & Hake 2012). Reversible histone modifications such as acetylation and methylation regulate transcription from genomic DNA, defining the 'readability' of genes in specific tissues (Kouzarides 2007, Marmorstein & Trievel 2009, Butler et al. 2012).
N.B. The coordinates of post-translational modifications represented here follow Reactome standardized naming, which includes the UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed; therefore the coordinates of post-translated histone residues described here are frequently +1 when compared with the literature. For more information on Reactome's standards for naming pathway events, the molecules that participate in them and representation of post-translational modifications, please refer to Naming Conventions on the Reactome Wiki or Jupe et al. 2014.
Chromatin organization refers to the composition and conformation of complexes between DNA, protein and RNA. It is determined by processes that result in the specification, formation or maintenance of the physical structure of eukaryotic chromatin. These processes include histone modification, DNA modification, and transcription. The modifications are bound by specific proteins that alter the conformation of chromatin.