This domain is found in eukaryotes, and is typically between 302 and 338 amino acids in length. It is found in association with and . Most members are promyelocytic leukemia proteins, and this family lies towards the C terminus. Proteins containing this domain include PML protein from mammals. PML (promyelocytic leukaemia) functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms [].
This superfamily consists of several Mastadenovirus E4 ORF3 proteins. Early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection. Both proteins facilitate efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. A unique function of E4 ORF3 is the reorganisation of nuclear structures known as PML oncogenic domains (PODs). This domain is annotated as pleiotropic. It is relevant to highlight that early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection which include efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. However, characterisation of E4 ORF3 has revealed several unique functions such as the reorganisation of nuclear structures known as PML oncogenic domains (PODs), which are nuclear structures whose function still remains unclear although these have been implicated in several critical cellular processes such as, regulation of transcription, apoptosis, transformation, and response to interferon [].
MAGE-A genes are a subfamily of the melanoma antigen genes (MAGEs), whose expression is restricted to tumour cells of different origin and normal tissues of the human germline [, ].MAGEA2 may act by binding histone deacetylase (HDAC) and repressing p53-dependent apoptosis. In addition to its anti-apoptotic effect, MAGEA2 may have a role in the early progression to malignancy by interfering with PML (promyelocytic leukemia) tumour suppressor/p53 function [].
Muscular LMNA-interacting protein (MLIP) is a muscle-enriched A-type Lamin-interacting protein, an innovation of amniotes, and is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localises with lamin A and C in the nuclear envelope. MLIP also co-localises with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP [].
This entry represents the replication protein A (RPA) interacting protein. RPA is a single stranded DNA-binding protein involved in DNA replication, repair, and recombination []. After synthesis in thecytoplasm, RPA is transported into the nucleus mediated by RPA interacting protein [, ]. In humans, RPA interacting protein has several splice isoforms, including hRIPalpha, hRIPbeta, hRIPgamma, hRIPdelta1, hRIPdelta2, and hRIPdelta3. hRIPbeta transports RPA into the PML nuclear body and releases RPA upon UV irradiation []. It seems that the number of splice isoforms of RIPalpha is species-specific and has a tendency to increase in higher eukaryotes [].
This family consists of several Mastadenovirus E4 ORF3 proteins. Early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection. Both proteins facilitate efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. A unique function of E4 ORF3 is the reorganisation of nuclear structures known as PML oncogenic domains (PODs). The function of these domains is unclear, but PODs have been implicated in a number of important cellular processes, including transcriptional regulation, apoptosis, transformation, and response to interferon [].
SMC6 is a core component of the SMC5-SMC6 complex [, ], a complex involved in repair of DNA double-strand breaks by homologous recombination []. In humans, the complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks []. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs) [].
SMC5 is a core component of the SMC5-SMC6 complex [, ], a complex involved in repair of DNA double-strand breaks by homologous recombination [, ]. In humans, the SMC5-SMC6 complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks []. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs) []. SMC5 is required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6 [].
Adenoviruses E4 is essential for DNA replication and late protein synthesis []. The adenovirus, early region 4 open reading frame 3 (E4 ORF3) protein is required for viral DNA replication during the interferon (IFN)-induced antiviral state [].The E4 ORF3 protein reorganises the promyelocytic leukemia (PML) protein nuclear bodies. These normally punctate structures are reorganised by E4 ORF3 into tracks that eventually surround viral replication centres. PML rearrangement is an evolutionarily conserved function of E4 ORF3 [].The product of adenovirus early region 4 (E4), open reading frame 6, is E4 34k. It modulates viral late gene expression, DNA replication, apoptosis, double strand break repair, and transformation through multiple interactions with components in infected and transformed cells [, ]. Conservation of several cysteine and histidine residues among E4 34k sequences suggests the presence of a zinc binding domain, which is important for its function [].
This entry represents the SKI/SnoN family of proteins, which are the products of the oncogenic sno gene. This gene was identified based on its homology to v-ski, the transforming component of the Sloan-Kettering virus. Both Ski and SnoN are potent negative regulators of TGF-beta []. Overexpression of Ski or SnoN results in oncogenic transformation of avian fibroblasts; however it may also result in terminal differentiation and therefore the Ski/SnoN mechanism of action is thought to be complex [].These proteins do not have catalytic or DNA-binding activity and therefore function primarily through interaction with other proteins, acting as transcriptional cofactors. Despite their lack of DNA-binding ability, their primary function is related to transcriptional regulation, in particular the negative regulation of TGF-beta signalling [, ]. Ski/SnoN interact concurrently with co-Smad and R-Smad and in doing so block the ability of the Smad complexes to activate transcription of the TGF-beta target genes []. Binding of Ski/SnoN may additionally stabilise the Smad heteromer on DNA, therefore preventing further binding of active Smad complexes []. As Smad complexes critically mediate the inhibitory signals of TGF-beta in epithelial cells, high levels of SKI/SnoN may promote cell proliferation. They repress gene transcription recruiting diverse corepressors and histone deacetylases and stablish cross-regulatory mechanisms with TGF-beta/Smad pathway that control the magnitude and duration of TGF-beta signals. The alteration in regulatory processes may lead to disease development [].High levels of SnoN have been shown to stabilise p53 with a resultant increase in premature senescence. SnoN interacts with the PML protein and is then recruited to the PML nuclear bodies, resulting in stabilisation of p53 and premature senescence [].
Daxx is a ubiquitously expressed protein that functions, in part, as a transcriptional co-repressor through its interaction with a growing numberof nuclear, DNA-associated proteins. Human Daxx contains four structural domains commonly found in transcriptional regulatory proteins: two predicted paired amphipathic helices, an acid-rich domain and a Ser/Pro/Thr (SPT)-rich domain. The post-translational modification status of the SPT-domain of hDaxx regulates its association with transcription factors such as Pax3 and ETS-1, effectively bringing hDaxx to sites of active transcription.Through its presence at the site of active transcription, hDaxx could then be able to associate with acetylated histones present in the nucleosomes andDek that is associated with chromatin. Through its association with the SPT-domain of hDaxx, histone deacetylases may also be brought to the site of active transcription. As a consequence, nucleosomes in the vicinity of the site of active transcription will have the histone tails deacetylated, allowing the deactylated tail to bind to DNA, thereby leading to an inactive chromatin structure and transcriptional repression []. The Daxx protein (also known as the Fas-binding protein or death domain-associated protein 6) is thought to play a role in apoptosis as a component of nuclear promyelocytic leukemia protein (PML) oncogenic domains (PODS). Daxx associates with PODs through a direct interaction withPML, a critical component of PODs. The interaction is a dynamic, cell cycle regulated event and is dependent on the post-translational modification of PML by the small ubiquitin-related modifier SUMO-1.
One of the largest protein families in the human genome is the zinc fingerfamily that contains members involved in the regulation of transcriptionprocesses. The zinc finger domains have been classified based on the order ofcysteine (C) and histidine (H) residues. Zinc fingers are thought to mediateprotein-DNA and protein-protein interactions. The ADD (ATRX, DNMT3, DNMT3L)domain is a cysteine-rich region that consists of a C2C2-type zinc finger anda closely located domain of an imperfect PHD-type zinc finger with C4C4. The region between the two subdomains has a constant length, andit contains identical and conserved amino acids [, ]. The ADD domain binds to the histone H3 tail that is unmethylated at lysine 4 [, ].The ADD domain is present in chromatin-associated proteins that play a role inestablishing and/or maintaining a normal pattern of DNA methylation:DNMT3A, DNMT3B, DNA methyltransferases.DNMT3L, a DNMT3-like enzymatically inactive regulatory factor.ATRX, a large nuclear protein predominantly localized to heterochromatinand nuclear PML bodies. At the C terminus is a helicase/ATPase domain, which characterises ATRX as a member of the SNF2 (SWI/SNF) family of chromatin-associated proteins. The ADD domain is composed of three clearly distinguishable modules that packtogether through extensive hydrophobic interactions to form a single globulardomain. Packed against this GATA-like finger is a second subdomain,which binds two zinc ions and closely resembles the structure reported forseveral PHD fingers. Finally, there is a long C-terminal α-helix that runsout from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain closetogether. This combination of fused GATA-like and PHD fingers within a singledomain is thus far unique [, ].
