Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.

• MeSH
• aktivní transport - buněčné jádro MeSH
• DNA nádorová genetika   metabolismus   MeSH
• HeLa buňky MeSH
• heteroduplexy nukleové kyseliny genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádory genetika   metabolismus   MeSH
• nestabilita genomu * MeSH
• polyadenylace MeSH
• poškození DNA * MeSH
• prekurzory RNA biosyntéza   genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• replikace DNA * MeSH
• RNA nádorová biosyntéza   genetika   MeSH
• štěpení RNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Účel přehledu: Astma a ďalšie genetické ochorenia sú komplexnými genetickými poruchami, ktoré vznikajú následkom interakcií medzi viacerými génmi a faktormi vonkajšieho prostredia. V nasledujúcom prehľadovom článku zhrnujeme nálezy analýz kandidátskych génov, diskutujeme o doterajších úspechoch celogenómových asociačných štúdií a načrtávame nové výzvy v tejto oblasti. Nové poznatky: V uplynulom roku bolo publikovaných päť celogenómových asociačných štúdií v oblasti astmy, jedna v oblasti atopickej dermatitídy a štyri štúdie intermediárnych fenotypov s použitím kvantitatívnych charakteristík lokusov. Tieto boli celkovo robustnejšie a vhodnejšie na replikáciu ako predchádzajúce štúdie s kandidátskymi génmi a umožnili identifikáciu nových lokusov pre astmu (t.j. 1q31, 9q21.31) aj pre atopickú dermatitídu (11q13). Súhrn: Integrácia výsledkov z nedávnych celogenómových asociačných štúdií s podrobnou analýzou asociácií kandidátskych génov potvrdila dôležitosť imunitnej detekcie a imunitných odpovedí sprostredkovaných Th2-bunkami v patogenéze alergického ochorenia a podnietila nový záujem o úlohu funkcie epitelovej bariéry a odpovedí na úrovni tkanív. Zdá sa, že celogenómové asociačné štúdie poskytujú solídnu cestu k identifikácii nových génových lokusov, ktoré prispievajú ku vnímavosti na dané ochorenie. Preskúmanie medzigénových interakcií a interakcií medzi génmi a vonkajším prostredím a objasnenie vplyvu epigenetického fenoménu na vnímavosť voči alergickému ochoreniu ostávajú dôležitými výzvami k pochopeniu komplexného charakteru astmy a ďalších alergických ochorení.

Asthma and other allergic diseases are complex genetic disorders that result from interactions between multiple genes and environmental factors. In this review, we summarize findings from candidate gene analyses, discuss the recent success of genome-wide association (GWA) studies, and outline challenges facing the field. RECENT FINDINGS: In the past year, five GWA studies have been reported for asthma, one for atopic dermatitis, and four for intermediate phenotypes using quantitative trait loci. These results have in general been more robust to replication than prior candidate gene studies, and have allowed the identification of novel loci for both asthma (i.e. 1q31, 9q21.31) and atopic dermatitis (11q13). SUMMARY: The integration of results from recent GWA studies with careful analyses of candidate gene associations studies has confirmed the importance of immune detection and TH2-cell mediated immune responses in the pathogenesis of allergic disease, and has raised new interest in the role of epithelial barrier function and tissue-level responses. GWA studies appear to provide a robust way to identify novel gene loci contributing to disease susceptibility. Dissecting gene-gene and gene-environment interactions, and exploring the contribution of epigenetic phenomena to allergic disease susceptibility remain important challenges to understanding the complex nature of asthma and other allergic diseases.

• MeSH
• atopická dermatitida genetika   imunologie   MeSH
• bronchiální astma genetika   imunologie   MeSH
• buněčná imunita genetika   MeSH
• celogenomová asociační studie MeSH
• epigeneze genetická imunologie   MeSH
• genetická epistáze imunologie   MeSH
• genové regulační sítě imunologie   MeSH
• lidé MeSH
• lokus kvantitativního znaku imunologie   MeSH
• náchylnost k nemoci MeSH
• Th2 buňky imunologie   MeSH
• vystavení vlivu životního prostředí MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

R-loops are three-stranded structures generated by annealing of nascent transcripts to the template DNA strand, leaving the non-template DNA strand exposed as a single-stranded loop. Although R-loops play important roles in physiological processes such as regulation of gene expression, mitochondrial DNA replication, or immunoglobulin class switch recombination, dysregulation of the R-loop metabolism poses a threat to the stability of the genome. A previous study in yeast has shown that the homologous recombination machinery contributes to the formation of R-loops and associated chromosome instability. On the contrary, here, we demonstrate that depletion of the key homologous recombination factor, RAD51, as well as RAD51 inhibition by the B02 inhibitor did not prevent R-loop formation induced by the inhibition of spliceosome assembly in human cells. However, we noticed that treatment of cells with B02 resulted in RAD51-dependent accumulation of R-loops in an early G1 phase of the cell cycle accompanied by a decrease in the levels of chromatin-bound ORC2 protein, a component of the pre-replication complex, and an increase in DNA synthesis. Our results suggest that B02-induced R-loops might cause a premature origin firing.

• MeSH
• chromozomální nestabilita účinky léků   MeSH
• DNA biosyntéza   MeSH
• G1 fáze účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• komplex rozpoznávající replikační počátek metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• R-smyčka * MeSH
• rekombinasa Rad51 * antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Collisions between replication and transcription machineries represent a significant source of genomic instability. RECQ5 DNA helicase binds to RNA-polymerase (RNAP) II during transcription elongation and suppresses transcription-associated genomic instability. Here, we show that RECQ5 also associates with RNAPI and enforces the stability of ribosomal DNA arrays. We demonstrate that RECQ5 associates with transcription complexes in DNA replication foci and counteracts replication fork stalling in RNAPI- and RNAPII-transcribed genes, suggesting that RECQ5 exerts its genome-stabilizing effect by acting at sites of replication-transcription collisions. Moreover, RECQ5-deficient cells accumulate RAD18 foci and BRCA1-dependent RAD51 foci that are both formed at sites of interference between replication and transcription and likely represent unresolved replication intermediates. Finally, we provide evidence for a novel mechanism of resolution of replication-transcription collisions wherein the interaction between RECQ5 and proliferating cell nuclear antigen (PCNA) promotes RAD18-dependent PCNA ubiquitination and the helicase activity of RECQ5 promotes the processing of replication intermediates.

• MeSH
• biologické modely MeSH
• DNA řízené RNA-polymerasy metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• DNA-dependentní DNA-polymerasy metabolismus   MeSH
• elongace genetické transkripce MeSH
• fyziologický stres genetika   MeSH
• genetická transkripce * MeSH
• HEK293 buňky MeSH
• helikasy RecQ metabolismus   MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• multienzymové komplexy metabolismus   MeSH
• otevřené čtecí rámce genetika   MeSH
• prekurzory RNA genetika   MeSH
• proliferační antigen buněčného jádra metabolismus   MeSH
• protein BRCA1 metabolismus   MeSH
• rekombinasa Rad51 metabolismus   MeSH
• replikace DNA * MeSH
• ribozomální DNA metabolismus   MeSH
• ubikvitinace MeSH
• ubikvitinligasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

"Genetics and Genomics in Medicine is a new textbook written for undergraduate and graduate students, as well as medical researchers, which explains the science behind the uses of genetics and genomics in medicine today. It is not just about rare inherited and chromosomal disorders, but how genetics affects the whole spectrum of human health and disease. DNA technologies are explained, with emphasis on the modern techniques that have revolutionized the use of genetic information in medicine and are indicating the role of genetics in common complex diseases. The detailed, integrative coverage of genetic approaches to treatment and prevention includes pharmacogenomics and the prospects for personalized medicine. Cancers are essentially genetic diseases and are given a dedicated chapter that includes new insights from cancer genome sequencing. Clinical disorders are covered throughout and there are extensive end-of-chapter questions and problems"--Provided by publisher.

This article provides data from a contemporary replication of Libet׳s experiment. For the methodology, results and discussion of the replication, see the article "Libet׳s Experiment: A Complex Replication" (Dominik et al., 2018). Three types of data are presented in this article: (1) introspective reports (M, W and S), (2) EMG onset times relative to a mouse click or to the target time in tasks with a movement at pre-set time and (3) relevant averaged EEG data.

• Publikační typ
• časopisecké články MeSH

• MeSH
• biochemie MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie
• NLK Publikační typ
• učebnice vysokých škol
• učebnice vysokých škol

• MeSH
• genetika MeSH

• Konspekt
• Obecná genetika. Obecná cytogenetika. Evoluce
• NLK Obory
• genetika, lékařská genetika

• MeSH
• biologie MeSH
• cytologie MeSH
• molekulární biologie MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• biologie
• NLK Publikační typ
• učebnice vysokých škol

Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, have been associated with neurodevelopmental and neurodegenerative disorders characterized by heterogeneous phenotypes with varying levels of clinical severity. However, the underlying molecular mechanisms of disease pathology remain poorly understood. Here, we show that BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex that processes 3' ends of various noncoding RNAs and pre-mRNAs. We find that Integrator functions are disrupted by BRAT1 deletion. In particular, defects in BRAT1 impede proper 3' end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and alter the expression of protein-coding genes. Importantly, impairments in Integrator function are also evident in patient-derived cells from BRAT1 related neurological disease. Collectively, our data suggest that defects in BRAT1 interfere with proper Integrator functions, leading to incorrect expression of RNAs and proteins, resulting in neurodegeneration.

• MeSH
• fenotyp MeSH
• histony MeSH
• jaderné proteiny * genetika   MeSH
• lidé MeSH
• mutace MeSH
• neurodegenerativní nemoci * genetika   MeSH
• posttranskripční úpravy RNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH