AT-rich interaction domain 1A gene (ARID1A) encodes for a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, a chromatin remodeling complex, and it has been implicated in the pathogenesis of various cancer types. In this review, we discuss how ARID1A is linked to endometrial cancer and what molecular pathways are affected by mutation or inhibition of ARID1A. We also discuss the potential use of ARID1A not only as a prognostic biomarker, but also as a target for therapeutic interventions. The dynamic modification of chromatin structure in a temporal-and spatial-specific manner determines cell fate by regulating expression levels of specific genes. The complexity of this process is further highlighted when considering all the endogenous and exogenous signals received by each cell during development and throughout its life. Numerous molecules (proteins and RNA) and macromolecular complexes are responsible for the organization of nucleosomes (Figure 1), epigenetic modifications, the dynamic change between the 'relaxed' or 'tight' conformation of chromatin (euchromatin and heterochromatin, respectively) and the accessibility of gene promoters determining cellular activities such as gene transcription, DNA repair and cell differentiation. Thus, disruption of normal chromatin remodeling impairs cellular development and homeostasis, and it has been associated extensively with tumorigenesis [reviewed in (1)]. The switch/sucrose non-fermentable (SWI/SNF) complex is a nucleosome-remodeling factor found in both eukaryotes and prokaryotes. It is involved in gene expression through transcriptional regulation and plays a pivotal role in carcinogenesis (2). This complex changes the DNA conformation in nucleosomes, allowing recruitment of transcription factors or other complexes responsible for DNA repair, replication and proliferation. Thus, when the SWI/SNF complex is disrupted, aberrant cell cycling is observed, as well as a loss of control of proliferation (3). SWI/SNF is a multi-subunit complex and many of its subunits, such AT-rich interaction domain 1A (ARID1A), ARID1B, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) and SMARCA4 (Figure 2), have been incriminated as driving mutations in various cancer types due to the high mutation frequencies observed (4). In particular, when considering human primary cancer cases with mutations in the SWI/SNF complex, most of the mutations seen are encountered in the gene encoding ARID1A (5-7). ARID1A and ARID1B genes encode DNA-targeting subunits, while SMARCA2 and SMARCA4 encode ATPase enzymes. The mutation frequency of these subunits in different cancer types seems to be tumor type-specific indicating that there is probably differential participation of the complex in gene regulation in different tissues (4). Loss of ARID1A has been shown in numerous human malignancies, such as uterine endometrioid carcinoma (8-10), ovarian endometrioid carcinoma (11), gastric cancer (12, 13), esophageal adenocarcinoma (14), pan...
STAT5 interacts with other factors to control transcription, and the mechanism of regulation is of interest as constitutive active STAT5 has been reported in malignancies. Here, LSD1 and HDAC3 were identified as novel STAT5a interacting partners in pro-B cells. Characterization of STAT5a, LSD1 and HDAC3 target genes by ChIP-seq and RNA-seq revealed gene subsets regulated by independent or combined action of the factors and LSD1/HDAC3 to play dual role in their activation or repression. Genes bound by STAT5a alone or in combination with weakly associated LSD1 or HDAC3 were enriched for the canonical STAT5a GAS motif, and such binding induced activation or repression. Strong STAT5 binding was seen more frequently in intergenic regions, which might function as distal enhancer elements. Groups of genes bound weaker by STAT5a and stronger by LSD1/HDAC3 showed an absence of the GAS motif, and were differentially regulated based on their genomic binding localization and binding affinities. These genes exhibited increased binding frequency in promoters, and in conjunction with the absence of GAS sites, the data indicate a requirement for stabilization by additional factors, which might recruit LSD1/HDAC3. Our study describes an interaction network of STAT5a/LSD1/HDAC3 and a dual function of LSD1/HDAC3 on STAT5-dependent transcription, defined by protein–protein interactions, genomic binding localization/affinity and motifs.
Dictyostelium discoideum nuclear RNase P is a ribonucleoprotein complex that displays similarities with its counterparts from higher eukaryotes such as the human enzyme, but at the same time it retains distinctive characteristics. In the present study, we report the molecular cloning and interaction details of DRpp29 and RNase P RNA, two subunits of the RNase P holoenzyme from D. discoideum. Electrophoretic mobility shift assays exhibited that DRpp29 binds specifically to the RNase P RNA subunit, a feature that was further confirmed by the molecular modeling of the DRpp29 structure. Moreover, deletion mutants of DRpp29 were constructed in order to investigate the domains of DRpp29 that contribute to and/or are responsible for the direct interaction with the D. discoideum RNase P RNA. A eukaryotic specific, lysine- and arginine-rich region was revealed, which seems to facilitate the interaction between these two subunits. Furthermore, we tested the ability of wild-type and mutant DRpp29 to form active RNase P enzymatic particles with the Escherichia coli RNase P RNA.
SummaryRNA molecules play critical roles in cell biology, and novel findings continuously broaden their functional repertoires. Apart from their well-documented participation in protein synthesis, it is now apparent that several noncoding RNAs (i.e., micro-RNAs and riboswitches) also participate in the regulation of gene expression. The discovery of catalytic RNAs had profound implications on our views concerning the evolution of life on our planet at a molecular level. A characteristic attribute of RNA, probably traced back to its ancestral origin, is the ability to interact with and be modulated by several ions and molecules of different sizes. The inhibition of ribosome activity by antibiotics has been extensively used as a therapeutical approach, while activation and substrate-specificity alteration have the potential to enhance the versatility of ribozyme-based tools in translational research. In this review, we will describe some representative examples of such modulators to illustrate the potential of catalytic RNAs as tools and targets in research and clinical approaches.
The effect of macrolide antibiotic spiramycin on RNase P holoenzyme and M1 RNA from Escherichia coli was investigated. Ribonuclease P (RNase P) is a ribozyme that is responsible for the maturation of 5' termini of tRNA molecules. Spiramycin revealed a dose-dependent activation on pre-tRNA cleavage by E. coli RNase P holoenzyme and M1 RNA. The K s and V max, as well as the K s(app) and V max(app) values of RNase P holoenzyme and M1 RNA in the presence or absence of spiramycin, were calculated from primary and secondary kinetic plots. It was found that the activity status of RNase P holoenzyme and M1 RNA is improved by the presence of spiramycin 18- and 12-fold, respectively. Primer extension analysis revealed that spiramycin induces a conformational change of the P10/11 structural element of M1 RNA, which is involved in substrate recognition.
Ribonuclease P (RNase P) is ubiquitous and essential Mg(2+)-dependent endoribonuclease that catalyzes the 5'-maturation of transfer RNAs. RNase P and the ribosome are so far the only ribozymes known to be conserved in all kingdoms of life. Eukaryotic RNase P activity has been detected in nuclei, mitochondria and chloroplasts and demonstrates great variability in sequence and subunit composition. In the last few years we have developed methodologies and pursued projects addressing the occurrence, distribution and the potential physiological role of RNase P in human epidermal keratinocytes. In view of the vital importance of lymphocytes for an effective immune system and their successful application after transfection with RNase P-associated external guide sequences in gene therapy, we concerned ourselves with the isolation and characterization of RNase P of peripheral human lymphocytes. We developed a method described herein, that will enable the study of the possible involvement of this ribozyme in the pathogenetic mechanisms of diverse autoimmune, inflammatory and neoplastic cutaneous disorders and may facilitate the further development of RNase P-based technology for gene therapy of infectious and neoplastic dermatoses.
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