Ino80 is evolutionarily conserved from yeast to man []. It is a ATPase and a subunit of Ino80 complex []. The Ino80 complex displays 3'-5' DNA helicase activity and is involved in transcription, DNA replication and repair, and chromatin remodelling [, , ].
This entry represents INO80 complex subunit 2 (Ies2), also known as INO80 complex subunit B (INO80B). INO80 is involved in transcriptional regulation, DNA replication and probably DNA repair []. Ies2 functions as a molecular switch that potently activates INO80 DNA-dependent ATPase activity [].
Ino80 subunit 1 (Ies1) is a component of the INO80 chromatin remodelling complex [].The INO80 complex is involved in transcriptional regulation, DNA replication and probably DNA repair. It remodels chromatin by increasing nucleosome mobility thus allowing access to enzymes that process DNA. Hydrolysis of ATP is required and the INO80 component is an ATPase []. The complex in yeast is composed of at least ARP4, ARP5, ARP8, RVB1, RVB2, TAF14, NHP10, IES1, IES3, IES4, IES6, ACT1, IES2, IES5 and INO80 [, ].
Proteins in this family are INO80 complex subunit E, a metazoan-specific subunit []. Subunit E is a putative regulatory component of the chromatin remodeling INO80 complex, which is involved in transcriptional regulation, DNA replication and probably DNA repair [].
INO80 complex subunit 3 (Iec3) is a component of the INO80 complex which remodels chromatin by shifting nucleosomes and is involved in DNA repair []. Interestingly, there is no Iec3 orthologue found in S. cerevisiae.
This entry represents INO80 complex subunit Ies6 (also known as INO80 complex subunit C, INO80C). INO80 is involved in transcriptional regulation, DNA replication and probably DNA repair []. Together with Arp5, Ies6 promotes binding of the INO80 complex to nucleosomes to help initiate the remodeling reaction []. The homologue from Arabidopsis ENN mediates a regulatory mechanism that monitors the expression of the essential multifunctional plant stress regulator EIN2 via H3K27me3 repressive histone demethylation and histone variant H2A.Z eviction, thus modulating responses to ethylene (ET), especially during embryogenesis [].
The INO80 ATPase is a member of the SNF2 family of ATPases and functions as an integral component of a multisubunit ATP-dependent chromatin remodelling complex. This family of proteins corresponds to the fungal Ies4 subunit of INO80.
The INO80 complex is involved in chromatin-remodelling by promoting the repositioning (sliding) or eviction of nucleosomes from the DNA in an ATP-dependent process. The INO80 chromatin-remodelling complex of Saccharomyces cerevisiae (Baker's yeast) is composed of at least 15 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae the core conserved subunits are: ATPase; Ino80.RuvB-like; Rvb1 and Rvb2.Actin; Act1.Actin-related: Arp4, Arp5 and Arp8.YEATS protein []; Taf14.The non-conserved subunits are: Ies1, Ies2, Ies3, Ies4, Ies5, Ies6 and Nhp10 []. The Ino80 ATPase is a member of the SNF2 family of ATPases and functions as an integral component of a multisubunit ATP-dependent chromatin remodelling complex that is conserved from yeast to mammals. Although INO80 complexes from yeast and higher eukaryotes share a common core of conserved subunits, the complexes have diverged substantially during evolution and have acquired new subunits with apparently species-specific functions. Studies in S. cerevisiae have shown that the conserved HSA (helicase) domain of the ATPase subunit, Ino80, is required for the binding of the Arp's and Act1, and this conserved module links the chromatin-remodelling complex to itssubstrate, the nucleosome [, ]. In eukaryotes the chromatin-remodelling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomer maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity [, , ].This entry represents the INO80 subunit 5 or Ies5, which has been shown to associate with the INO80 chromatin-remodelling complex under low-salt conditions [], though its function is unknown.
This is a group of proteins with a conserved C-terminal region which is found in INO80 complex subunit B (INO80B, Ies2 homologue, also known as PAPA-1). INO80B is a component of the INO80 complex which remodels chromatin by shifting nucleosomes and is involved in DNA repair [, ].
Nuclear factor related to kappa-B-binding protein, also known as INO80 complex subunit G, is a component of the metazoan INO80 complex involved in chromatin remodelling, transcription regulation, DNA replication and DNA repair [, ].
Actin-related protein 5 (Arp5) is proposed to be the core component of the chromatin remodeling INO80 complex, which is involved in transcriptional regulation, DNA replication and probably DNA repair [, ]. Together with Ies6, Arp5 promotes binding of the INO80 complex to nucleosomes to help initiate the remodeling reaction [].
This entry represents non-histone protein 10 (Nhp10, also known as Hmo2) from fungi. Nhp10 is a subunit of the non-essential INO80 chromatin remodelling complex, which contributes to transcription, DNA repair and DNA replication []. The interaction between Nhp10 and the DNA damage-induced phosphorylated histone H2A (gamma-H2AX) is required to recruit INO80 complex to a HO endonuclease-induced double-strand break []. Nhp10 binds to DNA ends and protect them from exonucleolytic cleavage []. It is related to the high-mobility group B (HMGB) proteins from mammals [].
This winged helix-like domain is found in nuclear factor related to kappa-B-binding (NFRKB) protein. NFRKB is a component of the metazoan INO80 complex involved in chromatin remodelling, transcription regulation, DNA replication and DNA repair. This winged helix-like domain is however not involved in DNA binding but is instead thought to be involved in protein-protein interactions [].
This winged helix-like domain is found in nuclear factor related to kappa-B-binding (NFRKB) protein. NFRKB is a component of the metazoan INO80 complex involved in chromatin remodelling, transcription regulation, DNA replication and DNA repair. This winged helix-like domain is however not involved in DNA binding but is instead thought to be involved in protein-protein interactions [].
YY1-associated protein 1 enhances transcription activation by the multifunctional zinc finger transcription factor YY1 []. It is also known as HCCA2 (hepatocellular carcinoma-associated gene 2). It is an oncogenic driver in hepatocellular carcinoma []and may play a role in cell cycle regulation []. It is component of the INO80 chromatin remodeling complex which is responsible for transcriptional regulation, DNA repair, and replication [].
TFPT, also known as INO80F or amida, plays an important role in p53-independent cellular apoptosis []. There is also evidence that it plays a role in cell cycle arrest and spermatogenesis [, ]. It is a putative regulatory component of the chromatin remodeling INO80 complex [].
This entry represents actin-related protein 8 and plant actin-related protein 9 (Arp8/plant Arp9). Plant Arp9 is a homologue of Arp8 []. Arp8 plays an important role in the functional organisation of mitotic chromosomes. It exhibits low basal ATPase activity, and it is unable to polymerise []. Arp8 is proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair [].
The ubiquitin C-terminal hydrolase (UCH; ubiquitinyl hydrolase; ubiquitin thiolesterase; MEROPS family C12) family of deubiquitinating enzymes (DUBs) consists of several members including: UCH-L1, UCH-L3, UCH-L5 (UCH37) and BRCA1-associated protein-1 (BAP1), all containing a conserved catalytic domain with cysteine peptidase activity []. UCH-L5 (UCH37; MEROPS identifier C12.005) is involved in the deubiquitinating activity in the 19S proteasome regulatory complex. It is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus []. UCH-L5 specifically cleaves 'Lys-48'-linked polyubiquitin chains [].
This entry represents RuvB-like proteins, including RuvB-like 1 and 2 (Rvb1 and Rvb2). Rvb1 is similar to Rvb2. They possesses ATP-dependent DNA helicase (5' to 3') activity []. They are components of the INO80 complex, which is involved in transcriptional regulation, DNA replication and probably DNA repair []. They are involved in multiple processes such as chromatin remodeling and pre-rRNA processing []. In mammals, they are components of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A [].
Proteins belonging to the SNF2 family of DNA dependent ATPases are important members of the chromatin remodelling complexes that are implicated in epigenetic control of gene expression. Members of the SNF2 family of proteinshave been identified in organisms ranging from Escherichia coli to Homo sapiens (Human). All of them contain the conserved SNF2 domain, which is defined by the existence of seven motifs (I, Ia, and II-VI) with sequences similarity to those motifs found in DNA and RNA helicases (see ). SNF2-like family members can be further subdivided into several subfamilies according to the presence of protein motifs outside of the ATPase region. The DBINO (DNA binding domain of INO80) domain is characteristic of the INO80 subfamily and is a DNA-binding domain [, ]. The DBINO domain is a 126 amino acid long peptide located near the N terminus, approximately 100 residues upstream of the SNF2 helicase domain. The presence of this domain in all the INO80 subfamily proteins from yeast to humans suggests its conserved function in evolution [, ].
This is the C-terminal domain found in eukaryotic UCH37 proteins (also known as Ubiquitin carboxyl-terminal hydrolase isozyme L5, UCHL5). UCH37 is a subunit of two complexes: INO80, which performs ATP-dependent sliding of nucleosomes for transcriptional regulation and DNA repair, and the 26S proteasome, which performs ATP-dependent proteolysis of polyubiquitylated proteins in the cytosol and nucleus. Recruitment to the proteasome is mediated by the C-terminal domain of RPN13 (also known as ADRM1). Recruitment to INO80 is mediated by the N-terminal domain of NFRKB. Structural and biochemical analysis reveal that RPN13 and NFRKB make similar interactions with the UCH37 C-terminal domain but have very different interactions with the catalytic UCH domain that are activating in the case of RPN13 and highly inhibitory in the case of NFRKB [].
RuvBL1 is a ubiquitously expressed protein that plays important roles in chromatin remodeling, transcription, DNA repair, and apoptosis. The significant evolutionary conservation of RuvBL1 from yeast to man strongly suggests that it mediates important cellular functions. RuvBL1 belongs to a large family of ATPases known as AAA proteins (ATPases associated with diverse cellular activities) which generally form hexamers. RuvBL1 is the eukaryotic homologue of the bacterial DNA-dependent ATPase and helicase RuvB [].RuvB-like helicase 2 (RUVBL2 or TIP49b; ) has single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity. It forms a homohexamer which is critical for ATP hydrolysis, and forms a dodecamer with RUVBL1 [, ]. RUVBL2 is an essential cofactor for oncogenic transformation by c-Myc []. It is a component of the NuA4 histone acetyltransferase [], BAF53 [], MLL1/MLL [], INO80 []and R2TP []complexes.This entry represents the second domain of RuvBL1 and RUVB2 which is involved in DNA/RNA binding [].
Microspherule protein 1 (MCRS1 or MSP58) is an RNA-binding protein that interacts with Daxx transcriptional regulator, relieving its repressor activity. Overexpression of MCRS1 leads to translocation of Daxx to the enlarged nucleoli in COS-1 or 293 cells []. It also interacts with fragile X messenger ribonucleoprotein 1 (FMRP), which represses specific mRNAs being transported as silent ribonucleoparticles from the cell body of a neuron to the distant synapse. MCRS1 binds to the G-quadruplex structures of the mRNA []. MCRS1 is a component of the NSL complex [], the MLL1/MLL complex [], and is a putative regulatory component in the chromatin remodeling INO80 complex []. The isoform MCRS2 is a cell-cycle-dependent protein which accumulates in the early S phase, and interacts with the telomerase-inhibitory protein LPTS/PinX1 [].
RuvB-like helicase 1 (RUVBL1 or TIP49a; ) has single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity. It forms a homohexamer which is critical for ATP hydrolysis, and forms a dodecamer with RUVBL2 [, ]. RUVBL1 is an essential cofactor for oncogenic transformation by c-Myc []. It is a component of the NuA4 histone acetyltransferase [], BAF53 [], MLL1/MLL [], INO80 []and R2TP []complexes.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
RuvB-like helicase 2 (RUVBL2 or TIP49b; ) has single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity. It forms a homohexamer which is critical for ATP hydrolysis, and forms a dodecamer with RUVBL1 [, ]. RUVBL2 is an essential cofactor for oncogenic transformation by c-Myc []. It is a component of the NuA4 histone acetyltransferase [], BAF53 [], MLL1/MLL [], INO80 []and R2TP []complexes.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
Th SWR1 complex is involved in chromatin-remodelling by promoting the the ATP-dependent exchange of histone H2A for the H2A variant HZT1 in Saccharomyces cerevisiae (Baker's yeast) or H2AZ in mammals. The SWR1 chromatin-remodelling complex is composed of at least 14 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae the core conserved subunits are: ATPase; Swr1.RuvB-like; Rvb1 and Rvb2.Actin; Act1.Actin-related: Arp4 and Arp6.YEATS protein []; Yaf9.The non-conserved subunits are: Vps71 (Swc6), Vps72 (Swc2), Swc3, Swc4, Swc5, Swc7, Bdf1 [].Seven of the SWR1 subunits are involved in maintaining complex integrity and H2AZ histone replacement activity: Swr1, Swc2, Swc3, Arp6, Swc5, Yaf9 and Swc6. Arp4 is required for the association of Bdf1, Yaf9, and Swc4 and Arp4 is also required for SWR1 H2AZ histone replacement activity in vitro. Furthermore the N-terminal region of the ATPase Swr1 provides the platform upon which Bdf1, Swc7, Arp4, Act1, Yaf9 and Swc4 associate []; it also contains an additional H2AZ-H2B specific binding site, distinct from the binding site of the Swc2 subunit []. In eukaryotes the deposition of variant histones into nucleosomes by the chromatin-remodelling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomer maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity. This entry represents the subunit Swc7; the smallestsubunit of the SWR1 complex. Swc7 is not required for H2AZ binding. Swc7 associates with the N terminus of Swr1, and the association of Bdf1 requires Swc7, Yaf9, and Arp4 [].
