CAPAM:the mRNA cap adenosine N6 methyltransferase

Predmet rada održivo je upravljanje zaštićenim prirodnim područjima u svijetu kao osnova za iznalaženje najprimjerenijeg modela upravljanja u Nacionalnom parku Plitvička jezera. Istraživački pristup temelji se na odgovarajućem metodološkom instrumentariju, s težištem na anketnom istraživanju i multivarijatnoj analizi. Istraživanjem je obuhvaćeno 114 zaštićenih prirodnih područja u svijetu te stanovništvo, posjetitelji i razvojni akteri u Nacionalnom parku Plitvička jezera i njegovoj okolici. Rezultat istraživanja sljedeće su zaključne postavke: 1. pod rastućim antropogenim utjecajima, u prvom redu turizma, zaštićena prirodna područja u svijetu suočena su sa sve većim problemom opterećenosti prostora; 2. na globalnoj razini postoje različiti modeli upravljanja prirodnim područjima, pri čemu se sve više ističe integralni model upravljanja; 3. Nacionalni park Plitvička jezera afirmirao se kao istaknuto žarište turističkog razvoja, s diferenciranim utjecajem na održivi razvoj: razmjerno pozitivnim utjecajem na socijalno-ekonomski razvoj, neznatnim utjecajem na demografske procese i izrazito negativnim utjecajem na ekološki sustav i krajolik; 4. Temeljem pozitivne prakse u zaštićenim prirodnim područjima svijeta, te specifičnosti i aktualnih problema održivog razvoja zaključno se predlaže primjena integralnog modela upravljanja u Parku, s tri prioritetne osi: a) ekološki prihvatljivo gospodarstvo s težištem na održivom turizmu, b) funkcionalna (re)organizacija i c) jačanje regionalne povezanostiThe subject of the dissertation is the sustainable management of protected natural areas in the world as a basis for finding the most appropriate management model for Plitvice Lakes National Park. The research approach is based on the appropriate methodological instruments, with a focus on the survey and multivariate analysis. The survey included 114 protected nature areas in the world and the population, visitors and developmental stakeholders in the Plitvice Lakes National Park and its surroundings. The result of research are following final settings: 1. under increasing anthropogenic impacts, primarily tourism, protected natural areas in the world are faced with the growing problem of impacts on space; 2. at the global level there are different models for managing natural areas, with the increasingly emphasizes on the integral management model; 3. Plitvice Lakes National Park established himself as a prominent focal point of tourism development, with differentiated impacts on sustainable development: the relatively positive impact on socio-economic development, relatively unaffecting the demographic processes and extremely negative impact on the ecosystem and landscape; 4. According to good practice in protected natural areas of the world, and the specifics of the current problems of sustainable development, finaly dissertation proposed application of the integrated management model in the Park, with three priority axes: a) environmentally friendly economy with a focus on sustainable tourism, b) functional (re) organizations and c) strengthening of regional integration

Regulation of mRNA capping in the cell cycle

The mRNA cap structure, which is added to nascent RNA pol II transcripts, recruits the protein complexes required for pre-mRNA transcript processing, mRNA export and translation initiation. The enzymes which catalyze mRNA cap synthesis are regulated by cellular signaling pathways which impact on their expression, localization and activity. Here we discuss the recent observation that the mRNA cap methyltransferase, RNMT, is phosphorylated on Thr-77 by CDK1-cyclin B1, which regulates its activity and the proteins with which it interacts. RNMT Thr-77 phosphorylation provides a burst of mRNA cap methyltransferase activity during early G1 phase at a time when transcription is reactivated following completion of the cell cycle. This co-ordination of transcription and mRNA capping makes an important contribution to gene expression in the cell; preventing RNMT Thr-77 phosphorylation inhibits cell proliferation. Here we discuss these findings and how mRNA cap synthesis may be regulated in other scenarios

Win Prediction in Esports: Mixed-Rank Match Prediction in Multi-player Online Battle Arena Games

Esports has emerged as a popular genre for players as well as spectators, supporting a global entertainment industry. Esports analytics has evolved to address the requirement for data-driven feedback, and is focused on cyber-athlete evaluation, strategy and prediction. Towards the latter, previous work has used match data from a variety of player ranks from hobbyist to professional players. However, professional players have been shown to behave differently than lower ranked players. Given the comparatively limited supply of professional data, a key question is thus whether mixed-rank match datasets can be used to create data-driven models which predict winners in professional matches and provide a simple in-game statistic for viewers and broadcasters. Here we show that, although there is a slightly reduced accuracy, mixed-rank datasets can be used to predict the outcome of professional matches, with suitably optimized configurations

RAM function is dependent on Kapβ2-mediated nuclear entry

Eukaryotic gene expression is dependent on the modification of the first transcribed nucleotide of pre-mRNA by the addition of the 7-methylguanosine cap. The cap protects transcripts from exonucleases and recruits complexes which mediate transcription elongation, processing and translation initiation. The cap is synthesized by a series of reactions which link 7-methylguanosine to the first transcribed nucleotide via a 5′ to 5′ triphosphate bridge. In mammals, cap synthesis is catalysed by the sequential action of RNGTT (RNA guanylyltransferase and 5′-phosphatase) and RNMT (RNA guanine-7 methyltransferase), enzymes recruited to RNA pol II (polymerase II) during the early stages of transcription. We recently discovered that the mammalian cap methyltransferase is a heterodimer consisting of RNMT and the RNMT-activating subunit RAM (RNMT-activating mini-protein). RAM activates and stabilizes RNMT and thus is critical for cellular cap methylation and cell viability. In the present study we report that RNMT interacts with the N-terminal 45 amino acids of RAM, a domain necessary and sufficient for maximal RNMT activation. In contrast, smaller components of this RAM domain are sufficient to stabilize RNMT. RAM functions in the nucleus and we report that nuclear import of RAM is dependent on PY nuclear localization signals and Kapβ2 (karyopherin β2) nuclear transport protein

Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells

Basic mechanisms in gene expression are currently being investigated as targets in cancer therapeutics. One such fundamental process is the addition of the cap to pre-mRNA, which recruits mediators of mRNA processing and translation initiation. Maturation of the cap involves mRNA cap guanosine N-7 methylation, catalysed by RNMT (RNA guanine-7 methyltransferase). In a panel of breast cancer cell lines, we investigated whether all are equivalently dependent on RNMT for proliferation. When cellular RNMT activity was experimentally reduced by 50%, the proliferation rate of non-transformed mammary epithelial cells was unchanged, whereas a subset of breast cancer cell lines exhibited reduced proliferation and increased apoptosis. Most of the cell lines which exhibited enhanced dependency on RNMT harboured oncogenic mutations in PIK3CA, which encodes the p110α subunit of PI3Kα. Conversely, all cell lines insensitive to RNMT depletion expressed wild-type PIK3CA. Expression of oncogenic PIK3CA mutants, which increase PI3K p110α activity, was sufficient to increase dependency on RNMT. Conversely, inhibition of PI3Kα reversed dependency on RNMT, suggesting that PI3Kα signalling is required. Collectively, these findings provide evidence to support RNMT as a therapeutic target in breast cancer and suggest that therapies targeting RNMT would be most valuable in a PIK3CA mutant background

mRNA cap methyltransferase, RNMT-RAM, promotes RNA pol II-dependent transcription

mRNA cap addition occurs early during RNA Pol II-dependent transcription, facilitating pre-mRNA processing and translation. We report that the mammalian mRNA cap methyltransferase, RNMT-RAM, promotes RNA Pol II transcription independent of mRNA capping and translation. In cells, sublethal suppression of RNMT-RAM reduces RNA Pol II occupancy, net mRNA synthesis, and pre-mRNA levels. Conversely, expression of RNMT-RAM increases transcription independent of cap methyltransferase activity. In isolated nuclei, recombinant RNMT-RAM stimulates transcriptional output; this requires the RAM RNA binding domain. RNMT-RAM interacts with nascent transcripts along their entire length and with transcription-associated factors including the RNA Pol II subunits SPT4, SPT6, and PAFc. Suppression of RNMT-RAM inhibits transcriptional markers including histone H2BK120 ubiquitination, H3K4 and H3K36 methylation, RNA Pol II CTD S5 and S2 phosphorylation, and PAFc recruitment. These findings suggest that multiple interactions among RNMT-RAM, RNA Pol II factors, and RNA along the transcription unit stimulate transcription. The mammalian mRNA cap methyltransferase, RNMT-RAM, prepares pre-mRNA for processing and translation and regulates expression of a subset of mRNAs. Here, Varshney et al. report that RNMT-RAM regulates transcription independent of mRNA cap methylation and translation. RNMT-RAM binds the full length of pre-mRNA and recruits proteins associated with transcription