Human SIRT1, an NAD+-dependent deacetylase, plays a role in cell death/ survival, senescence, and endocrine signalling []. Its substrates are well characterised, but evidence for the identity of its direct regulators has been wanting. Recently, the nuclear protein AROS (also termed 40S ribosomal protein S19-binding protein 1 []) has been implicated in the direct regulation of SIRT1 function - this protein has been dubbed 'active regulator of SIRT1. The protein has been shown to enhance SIRT1-mediated deacetylation of p53, in vitro and in vivo, and to inhibit p53-mediated transcriptional activity. It is the first direct SIRT1 regulator to have been identified that modulates p53-mediated growth regulation.
Cell cycle and apoptosis regulator protein 2 (CCAR2, also known as DBC-1) regulates biological processes such as transcription, heterochromatin formation, metabolism, mRNA splicing, apoptosis, and cell proliferation []. It is a core component of the DBIRD complex, which affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions []. It binds to SIRT1 and is a negative regulator of SIRT1 []. DBC-1 has been implicated in tumorigenesis [].
Hypermethylated in cancer 1 (HIC1) is a transcriptional repressor that modulates P53-dependent and E2F1-dependent cell growth control and is epigenetically inactivated in various human cancers []. It recognises and binds to the consensus sequence '5-[CG]NG[CG]GGGCA[CA]CC-3' []. It is a direct transcriptional repressor of ephrin-A1 and CXCR7, which are implicated in the pathogenesis of different cancers [, ]. HIC1 is also involved in down-regulation of SIRT1 and thereby is involved in regulation of p53/TP53-dependent apoptotic DNA-damage responses []. HIC1 interacts with several different corepressors such as CTBP1, CTBP2 and MTA1 (a subunit of the NuRD complex) [].
This group represents a core histone macro-H2A.MacroH2A is a variant of the major-type core histone H2A which contains an N-terminal H2A domain and a C-terminal nonhistone macro domain. Histone macroH2A is enriched on the inactive X chromosome of mammalian female cells []. It does not bind poly ADP-ribose, but does bind the monomeric SirT1 metabolite O-acetyl-ADP-ribose (OAADPR) with high affinity through its macro domain []. In addition, the macro domain of macroH2A associates with histone deacetylases and affects the acetylation status of nucleosomes. MacroH2A-containing nucleosomes are repressive toward transcription [].
Cell division cycle and apoptosis regulator protein 1 (CCAR1) associates with components of the Mediator and p160 coactivator complexes that play a role as intermediaries transducing regulatory signals from upstream transcriptional activator proteins to basal transcription machinery. CCAR1 also functions as a p53 coactivator and regulates expression of key proliferation-inducing genes [].Cell cycle and apoptosis regulator protein 2 (CCAR2, also known as DBC-1) regulates biological processes such as transcription, heterochromatin formation, metabolism, mRNA splicing, apoptosis, and cell proliferation []. It is a core component of the DBIRD complex, which affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions []. It binds to SIRT1 and is a negative regulator of SIRT1 []. DBC-1 has been implicated in tumorigenesis [].This entry also includes protein SHORT ROOT IN SALT MEDIUM 1 (RSA1, also known as EMB1579) from Arabidopsis. It regulates the transcription of several genes involved in the detoxification of reactive oxygen species generated by salt stress and the SOS1 gene that encodes a plasma membrane Na(+)/H(+) antiporter essential for salt tolerance []. RSA1 is localised to the nucleus and the loss of function of RSA1 affects global transcription and mRNA splicing [].
Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) () phosphorylates serine, threonine and tyrosine residues in proteins such as CRY2, FOXO1 and SIRT1 [, , , ]. It can be activated by tyrosine autophosphorylation [, ]. DYRK1A play a role in a signaling pathway regulating nuclear functions of cell proliferation. DYRK1A is a neurogenesis regulator and plays an important role in altered brain development in Down syndrome [, ]. Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B also known as Mirk) also phosphorylates serine, threonine and tyrosine residues, and has been shown to enhance the transcriptional activity of HNF1A and FOXO1 []. Mirk is reported to be an inhibitor of epithelial cell migration [], and appears to mediate carcinoma cell survival in specific environments [].This entry also includes mnb from Drosophila melanogaster. It plays a role in the specific control of proper proliferation of optic lobe neuronal progeny [].
Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) () phosphorylates serine, threonine and tyrosine residues in proteins such as CRY2, FOXO1 and SIRT1 [, , , ]. It can be activated by tyrosine autophosphorylation [, ]. DYRK1A play a role in a signaling pathway regulating nuclear functions of cell proliferation. DYRK1A is a neurogenesis regulator and plays an important role in altered brain development in Down syndrome [, ]. Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B also known as Mirk) also phosphorylates serine, threonine and tyrosine residues, and has been shown to enhance the transcriptional activity of HNF1A and FOXO1 []. Mirk is reported to be an inhibitor of epithelial cell migration [], and appears to mediate carcinoma cell survival in specific environments [].This entry also includes mnb from Drosophila melanogaster. It plays a role in the specific control of proper proliferation of optic lobe neuronal progeny [].This entry represents the catalytic domain found in DYRK1A and DYRK1B.
MacroH2A is a variant of the major-type core histone H2A which contains an N-terminal H2A domain and a C-terminal nonhistone macro domain. Histone macroH2A is enriched on the inactive X chromosome of mammalian female cells []. It does not bind poly ADP-ribose, but does bind the monomeric SirT1 metabolite O-acetyl-ADP-ribose (OAADPR) with high affinity through its macro domain []. In addition, the macro domain of macroH2A associates with histone deacetylases and affects the acetylation status of nucleosomes. MacroH2A-containing nucleosomes are repressive toward transcription [].The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes [].
PIAS3 is an E3-type small ubiquitin-like modifier (SUMO) ligases, stabilising the interaction between UBE2I and Ubc9 respectively and the substrate, and as a SUMO-tethering factor. It plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway [, , , ].PIAS3 sumoylates CCAR2, promoting its interaction with SIRT1 []and diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus [].SUMO proteins are ubiquitin like proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMO is first activated in an ATP-dependent reaction by formation of a thioester bond with an E1 (SUMO-activating) enzyme and then transferred to the SUMO conjugating (E2) enzyme Ubc9. Ubc9 catalyses the formation of an isopeptide bond between the C-terminal of SUMO and the amino group of lysine in the target protein. Sumoylated proteins can be targeted for different cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability [].
