Transcription-mediated replication hindrance: a major driver of genome instability

Genome replication involves dealing with obstacles that can result from DNA damage but also from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops. Experimental evidence reveals that an engaged transcription machinery at the DNA can either enhance such obstacles or be an obstacle itself. Thus, transcription can become a potentially hazardous process promoting localized replication fork hindrance and stress, which would ultimately cause genome instability, a hallmark of cancer cells. Understanding the causes behind transcription–replication conflicts as well as how the cell resolves them to sustain genome integrity is the aim of this review

Tourism Climatology: Past, Present and Future

Founded in 1999 at the 15th International Congress of Biometeorology, the Commission on Climate, Tourism and Recreation (CCTR) is an international working group that seeks to advance the current state of knowledge in the field of tourism/recreation climatology. Beginning in the 1970s, climatologists explored how climate impacts a myriad of economic sectors, including tourism, with research predominantly centered on how climatological information could be used within the context of tourism planning processes (Lamb 2002). After a brief decline in research activity in the 1980s, a new phase of research growth, propelled by climate change, emerged in the 1990s (Scott & Lemieux 2010). As noted by de Freitas (2017), the field is now truly multidisciplinary, with a range of disciplines contributing diverse methodologies to understand the climate and tourism nexus. Over the past five decades, the two-way relationship between climate and tourism that was once assumed is now empirically observed, objectively tested, and incorporates concepts and theoretical frameworks that support continued model development and global comparisons. The CCTR has facilitated and engaged the growing number of researchers in the field, building collaborative partnerships with industry leaders, identifying key knowledge gaps, and setting research priorities to continually advance the state of knowledg

Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion

Genome stability involves accurate replication and DNA repair. Broken replication forks, such as those encountering a nick, lead to double strand breaks (DSBs), which are preferentially repaired by sister-chromatid recombination (SCR). To decipher the role of chromatin in eukaryotic DSB repair, here we analyze a collection of yeast chromatin-modifying mutants using a previously developed system for the molecular analysis of repair of replication-born DSBs by SCR based on a mini-HO site. We confirm the candidates through FLP-based systems based on a mutated version of the FLP flipase that causes nicks on either the leading or lagging DNA strands. We demonstrate that Rpd3L and Hda1 histone deacetylase (HDAC) complexes contribute to the repair of replication-born DSBs by facilitating cohesin loading, with no effect on other types of homology-dependent repair, thus preventing genome instability. We conclude that histone deacetylation favors general sister chromatid cohesion as a necessary step in SCR

R-loops do not accumulate in transcription-defective hpr1-101 mutants: implications for the functional role of THO/TREX

To get further insight into the effect that THO/TREX and R-loops have in transcription-associated recombination and transcription, we analyzed the ability to form R-loops of hpr1-101, a THO mutation that impairs transcription and mRNP biogenesis without triggering hyper-recombination. Human AID, a cytidine deaminase that acts on ssDNA displaced by RNA-DNA hybrids, strongly induced both hyper-recombination and hyper-mutation in hpr1-101, similar to hpr1Δ mutants. However, in contrast to hpr1Δ, AID-induced mutations in hpr1-101 occur at similar frequencies in both the transcribed and non-transcribed strands, implying that the enhanced AID action in these mutants is not caused by co-transcriptional R-loops. These results indicate for the first time that THO has a transcriptional function that is not mediated by R-loops, providing a new perspective for the understanding of the coupling of transcription with mRNP biogenesis and export

Rpd3l contributes to the DNA damage sensitivity of saccharomyces cerevisiae checkpoint mutants

DNA replication forks that are stalled by DNA damage activate an S-phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the EXO1 gene. Using a whole-genome sequencing approach, we identified two additional genes, RXT2 and RPH1, whose mutation can also partially suppress this DNA damage sensitivity. We provide evidence that RXT2 and RPH1 act in a common pathway, which is distinct from the EXO1 pathway. Analysis of additional mutants indicates that suppression works through the loss of the Rpd3L histone deacetylase complex. Our results suggest that the loss or absence of histone acetylation, perhaps at stalled forks, may contribute to cell death in the absence of a functional checkpoint.Cancer Research UK FC001066UK Medical Research Council FC001066Wellcome Trust FC001066European Molecular Biology Organization ALTF 263–2011European Research Council Advanced 669424-CHROMORE

¿Dividir? No, gracias. El miedo a los números y el bajo rendimiento en matemáticas

Las personas que temen a los números suelen tener menos habilidades matemáticas. ¿Podría estar relacionado con pensamientos intrusivos generados por la ansiedad ante las matemáticas? ¿Se trata, más bien, de una mayor dificultad para procesar las cantidades en la línea numérica mental? ¿Existe alguna huella fisiológica de dicha dificultad? Entender cómo la ansiedad matemática afecta a la realización de operaciones numéricas puede permitir a las instituciones educativas y a la sociedad abordar este frecuente fenómeno de una manera más adecuada y eficiente, evitando las consecuencias negativas que acaba teniendo a largo plazo. En el presente artículo repasamos recientes hallazgos a este respecto

DNA-RNA hybrids: The risks of DNA breakage during transcription

Although R loops can occur at different genomic locations, the factors that determine their formation and frequency remain unclear. Emerging evidence indicates that DNA breaks stimulate DNA-RNA hybrid formation. Here, we discuss the possibility that formation of hybrids may be an inevitable risk of DNA breaks that occur within actively transcribed regions. While such hybrids must be removed to permit repair, their potential role as repair intermediates remains to be established

AID Induces Double-Strand Breaks at Immunoglobulin Switch Regions and c-MYC Causing Chromosomal Translocations in Yeast THO Mutants

Transcription of the switch (S) regions of immunoglobulin genes in B cells generates stable R-loops that are targeted by Activation Induced Cytidine Deaminase (AID), triggering class switch recombination (CSR), as well as translocations with c-MYC responsible for Burkitt's lymphomas. In Saccharomyces cerevisiae, stable R-loops are formed co-transcriptionally in mutants of THO, a conserved nuclear complex involved in mRNP biogenesis. Such R-loops trigger genome instability and facilitate deamination by human AID. To understand the mechanisms that generate genome instability mediated by mRNP biogenesis impairment and by AID, we devised a yeast chromosomal system based on different segments of mammalian S regions and c-MYC for the analysis of chromosomal rearrangements in both wild-type and THO mutants. We demonstrate that AID acts in yeast at heterologous S and c-MYC transcribed sequences leading to double-strand breaks (DSBs) which in turn cause chromosomal translocations via Non-Homologous End Joining (NHEJ). AID–induced translocations were strongly enhanced in yeast THO null mutants, consistent with the idea that AID–mediated DSBs depend on R-loop formation. Our study not only provides new clues to understand the role of mRNP biogenesis in preventing genome rearrangements and the mechanism of AID-mediated genome instability, but also shows that, once uracil residues are produced by AID–mediated deamination, these are processed into DSBs and chromosomal rearrangements by the general and conserved DNA repair functions present from yeast to human cells

Elaboración de una guía para la prevención de riesgos laborales en las prácticas de química

Este Trabajo Fin de Grado se centra en la elaboración de una guía para la prevención de riesgos laborales de las prácticas impartidas por el departamento de Ingeniería Química y Ambiental de la Escuela Técnica Superior de Ingeniería. De cada una de las prácticas se han identificado los riesgos y propuesto las medidas preventivas necesarias para eliminarlos, o en su caso, reducirlos. De esta manera, se pretende conseguir que todo el personal de laboratorio, maestros de taller, alumnos y becarios, efectúen las prácticas con total seguridad sin riesgo de que pueda ocurrir ningún accidente/incidente.This end of course project focuses on the design of a health and safety guide for the Chemical and Environmental Engineering Department at the school for Higher Level Engineering. Health and Safety issues, and their subsequent preventative measures have been detected for each practice with the aim of eliminating them, or should this be impossible, reducing the level of associated risk. By doing so this guide aims to ensure that laboratory practices are carried out in complete safety, without risk of accidents.Universidad de Sevilla. Grado en Ingeniería Químic