The intrinsically disordered, epigenetic factor RYBP binds to the citrullinating enzyme PADI4 in cancer cells

14 p.-6 fig.-1 tab.RYBP (Ring1 and YY 1 binding protein) is a multifunctional, intrinsically disordered protein (IDP), best described as a transcriptional regulator. It exhibits a ubiquitin-binding functionality, binds to other transcription factors, and has a key role during embryonic development. RYBP, which folds upon binding to DNA, has a Zn-finger domain at its N-terminal region. By contrast, PADI4 is a well-folded protein and it is one the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline. As both proteins intervene in signaling pathways related to cancer development and are found in the same localizations within the cell, we hypothesized they may interact. We observed their association in the nucleus and cytosol in several cancer cell lines, by using immunofluorescence (IF) and proximity ligation assays (PLAs). Binding also occurred in vitro, as measured by isothermal titration calorimetry (ITC) and fluorescence, with a low micromolar affinity (~1 μM). AlphaFold2-multimer (AF2) results indicate that PADI4's catalytic domain interacts with the Arg53 of RYBP docking into its active site. As RYBP sensitizes cells to PARP (Poly (ADP-ribose) polymerase) inhibitors, we applied them in combination with an enzymatic inhibitor of PADI4 observing a change in cell proliferation, and the hampering of the interaction of both proteins. This study unveils for the first time the possible citrullination of an IDP, and suggests that this new interaction, whether it involves or not citrullination of RYBP, might have implications in cancer development and progression.This research was funded by Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033/ and “ERDF A way of Making Europe” [PID2021-127296OB-I00 to AVC; and PDC2022-133952-I00 to EF]; by Instituto de Salud Carlos III co-funded by European Social Fund “Investing in your future” [CP19/00095 to CdJ] [PI22/00824 to MS and CdJ] [PI18/00394 to OA]; by Diputación General de Aragón [“Protein targets and Bioactive Compounds group” E45-20R to AVC, and “Digestive Pathology Group” B25-20R to OA], and by Consellería de Innovación, Universidades, Ciencia y Sociedad Digital (Generalitat Valenciana) [CAICO 2021/0135 to CdJ and JLN].Peer reviewe

A collaboratively derived environmental research agenda for Galapagos

Galápagos is one of the most pristine archipelagos in the world and its conservation relies upon research and sensible management. In recent decades both the interest in, and the needs of, the islands have increased, yet the funds and capacity for necessary research have remained limited. It has become, therefore, increasingly important to identify areas of priority research to assist decision-making in Galápagos conservation. This study identified 50 questions considered priorities for future research and management. The exercise involved the collaboration of policy makers, practitioners and researchers from more than 30 different organisations. Initially, 360 people were consulted to generate 781 questions. An established process of preworkshop voting and three rounds to reduce and reword the questions, followed by a two-day workshop, was used to produce the final 50 questions. The most common issues raised by this list of questions were human population growth, climate change and the impact of invasive alien species. These results have already been used by a range of organisations and politicians and are expected to provide the basis for future research on the islands so that its sustainability may be enhanced. </jats:p

Conflict in the Application of Tax Norms and Related Figures. Current Issues

Trabajo de fin de Grado. Grado en Derecho. Curso académico 2015-2016[ES] La elusión fiscal es una cuestión que hoy día ocupa grandes titulares. Es necesario hacer una revisión a las diferentes figuras que configuran las prácticas de minoración de las obligaciones tributarias. Con un análisis de estas figuras obtenemos una visión global de los diferentes instrumentos que poseen todos los contribuyentes. Así observaremos cómo hay ciertas figuras que propician ese ahorro fiscal de una manera lícita, acorde a las leyes. En cambio, observamos cómo hay ciertas figuras que se usan con el fin de minorar la deuda tributaria de una manera ilícita. A su vez, también observaremos cómo existe también un método consistente en realizar operaciones con el fin de conseguir dicha reducción que no se puede dilucidar fácilmente si es legítima o vulnera el espíritu que rigen las normas tributarias[EN] Tax avoidance is a question which worries many large title holders. It is necessary to inspect the different figures which form the practice of reducing tax liability. With the analysis of these figures, we gain a global vision of the different tools owned by the tax payers. In this way, we will observe how there are certain figures that provide tax savings in a just ways, according to law. Furthermore, we will observe how certain figures which are used in order to deduct tax debt in a just way. At the same time, we will observe how there is also a consistent method for carrying out operations, with the aim to achieve the aforementioned reduction, which cannot be easily explained whether they are legitimate or infringe the spirit which governs tax norms

Roles of Polycomb complexes in regulating gene expression and chromatin structure in plants

The evolutionary conserved Polycomb Group (PcG) repressive system comprises two central protein complexes, PcG repressive complex 1 (PRC1) and PRC2. These complexes, through the incorporation of histone modifications on chromatin, have an essential role in the normal development of eukaryotes. In recent years, a significant effort has been made to characterize these complexes in the different kingdoms, and despite there being remarkable functional and mechanistic conservation, some key molecular principles have diverged. In this review, we discuss current views on the function of plant PcG complexes. We compare the composition of PcG complexes between animals and plants, highlight the role of recently identified plant PcG accessory proteins, and discuss newly revealed roles of known PcG partners. We also examine the mechanisms by which the repression is achieved and how these complexes are recruited to target genes. Finally, we consider the possible role of some plant PcG proteins in mediating local and long-range chromatin interactions and, thus, shaping chromatin 3D architecturePeer reviewe

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets