SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability.

During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.

DICER ribonuclease removes harmful R-loops.

R-loops, which consist of a DNA-RNA hybrid and a displaced DNA strand, are known to threaten genome integrity. To counteract this, different mechanisms suppress R-loop accumulation by either preventing the hybridization of RNA with the DNA template (RNA biogenesis factors), unwinding the hybrid (DNA-RNA helicases), or degrading the RNA moiety of the R-loop (type H ribonucleases [RNases H]). Thus far, RNases H are the only nucleases known to cleave DNA-RNA hybrids. Now, we show that the RNase DICER also resolves R-loops. Biochemical analysis reveals that DICER acts by specifically cleaving the RNA within R-loops. Importantly, a DICER RNase mutant impaired in R-loop processing causes a strong accumulation of R-loops in cells. Our results thus not only reveal a function of DICER as an R-loop resolvase independent of DROSHA but also provide evidence for the role of multi-functional RNA processing factors in the maintenance of genome integrity in higher eukaryotes.

The NED foundation experience: A model of global neurosurgery.

Introduction: The Neurosurgery Education and Development (NED) Foundation (NEDF) started the development of local neurosurgical practice in Zanzibar (Tanzania) in 2008. More than a decade later, multiple actions with humanitarian purposes have significantly improved neurosurgical practice and education for physicians and nurses. Research question: To what extent could comprehensive interventions (beyond treating patients) be effective in developing global neurosurgery from the outset in low and middle-income countries? Material and method: A retrospective review of a 14- year period (2008-2022) of NEDF activities highlighting landmarks, projects, and evolving collaborations in Zanzibar was carried out. We propose a particular model, the NEDF model, with interventions in the field of health cooperation that have simultaneously aimed to equip, treat, and educate in a stepwise manner. Results: 138 neurosurgical missions with 248 NED volunteers have been reported. In the NED Institute, between Nov 2014-Nov 2022, 29635 patients were seen in the outpatient clinics and 1985 surgical procedures were performed. During the course of NEDF's projects, we have identified three different levels of complexity (1, 2 and 3) that include the areas of equipment ("equip"), healthcare ("treat") and training ("educate"), facilitating an increase of autonomy throughout the process. Discussion and Conclusion: In the NEDF's model, the interventions required in each action area (ETE) are coherent for each level of development (1, 2 and 3). When applied simultaneously, they have a greater impact. We believe the model can be equally useful for the development of other medical and/or surgical specialties in other low-resource healthcare settings.

Spontaneous deamination of cytosine to uracil is biased to the non-transcribed DNA strand in yeast.

Transcription in Saccharomyces cerevisiae is associated with elevated mutation and this partially reflects enhanced damage of the corresponding DNA. Spontaneous deamination of cytosine to uracil leads to CG>TA mutations that provide a strand-specific read-out of damage in strains that lack the ability to remove uracil from DNA. Using the CAN1 forward mutation reporter, we found that C>T and G>A mutations, which reflect deamination of the non-transcribed and transcribed DNA strands, respectively, occurred at similar rates under low-transcription conditions. By contrast, the rate of C>T mutations was 3-fold higher than G>A mutations under high-transcription conditions, demonstrating biased deamination of the non-transcribed strand (NTS). The NTS is transiently single-stranded within the ∼15 bp transcription bubble, or a more extensive region of the NTS can be exposed as part of an R-loop that can form behind RNA polymerase. Neither the deletion of genes whose products restrain R-loop formation nor the over-expression of RNase H1, which degrades R-loops, reduced the biased deamination of the NTS, and no transcription-associated R-loop formation at CAN1 was detected. These results suggest that the NTS within the transcription bubble is a target for spontaneous deamination and likely other types of DNA damage.

DDX47, MeCP2, and other functionally heterogeneous factors protect cells from harmful R loops.

Unscheduled R loops can be a source of genome instability, a hallmark of cancer cells. Although targeted proteomic approaches and cellular analysis of specific mutants have uncovered factors potentially involved in R-loop homeostasis, we report a more open screening of factors whose depletion causes R loops based on the ability of activation-induced cytidine deaminase (AID) to target R loops. Immunofluorescence analysis of γH2AX caused by small interfering RNAs (siRNAs) covering 3,205 protein-coding genes identifies 59 potential candidates, from which 13 are analyzed further and show a significant increase of R loops. Such candidates are enriched in factors involved in chromatin, transcription, and RNA biogenesis and other processes. A more focused study shows that the DDX47 helicase is an R-loop resolvase, whereas the MeCP2 methyl-CpG-binding protein uncovers a link between DNA methylation and R loops. Thus, our results suggest that a plethora of gene dysfunctions can alter cell physiology via affecting R-loop homeostasis by different mechanisms.

A role for the Saccharomyces cerevisiae Rtt109 histone acetyltransferase in R-loop homeostasis and associated genome instability.

The stability of the genome is occasionally challenged by the formation of DNA-RNA hybrids and R-loops, which can be influenced by the chromatin context. This is mainly due to the fact that DNA-RNA hybrids hamper the progression of replication forks, leading to fork stalling and, ultimately, DNA breaks. Through a specific screening of chromatin modifiers performed in the yeast Saccharomyces cerevisiae, we have found that the Rtt109 histone acetyltransferase is involved in several steps of R-loop-metabolism and their associated genetic instability. On the one hand, Rtt109 prevents DNA-RNA hybridization by the acetylation of histone H3 lysines 14 and 23 and, on the other hand, it is involved in the repair of replication-born DNA breaks, such as those that can be caused by R-loops, by acetylating lysines 14 and 56. In addition, Rtt109 loss renders cells highly sensitive to replication stress in combination with R-loop-accumulating THO-complex mutants. Our data evidence that the chromatin context simultaneously influences the occurrence of DNA-RNA hybrid-associated DNA damage and its repair, adding complexity to the source of R-loop-associated genetic instability.

WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage.

Perturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability.

Genome-Wide Analysis of DNA-RNA Hybrids in Yeast by DRIPc-Seq and DRIP-Seq.

DNA-RNA hybrids are required for several natural processes in the cell, such as replication and transcription. However, the misregulation of its metabolism is an important source of genetic instability, a hallmark of diseases including cancer. For this reason, genome-wide detection of DNA-RNA hybrids is becoming essential to identify new factors that play a role in its formation or resolution and to understand the global changes in its dynamics because of genetic alterations or chemical treatments. Here, we describe two different immunoprecipitation-based procedures for the genome-wide profiling of DNA-RNA hybrids in the yeast Saccharomyces cerevisiae: DRIP-seq and DRIPc-seq.

Optimism as a protective factor against the psychological impact of COVID-19 pandemic through its effects on perceived stress and infection stress anticipation.

The 2019 coronavirus disease (COVID-19) and the recommended social isolation presented a challenge to people's mental health status. Optimism is a psychological factor that plays a key role in the evaluation of stressful situations. The purpose of this study was to investigate the mediating role of perceived stress and Covid-19-related stress anticipation in the relationship between optimism and post-traumatic stress symptoms. Our sample included 1015 participants ranging in age from 18 to 79 years, 80% of whom were Spaniards. At the beginning of the worldwide pandemic, participants were confined to their homes for at least seven days and completed an online survey measuring various sociodemographic and psychological variables. We found an indirect effect of optimism on intrusion and hyperarousal through perceived stress and stress anticipation. In addition, we observed an indirect effect of optimism on avoidance through perceived stress. Finally, the results showed a significant indirect effect of optimism on the total post-traumatic stress symptoms score through perceived stress and stress anticipation. Our results indicate that positive beliefs inherent to optimism are related to less psychological impact of the COVID-19 outbreak.

VID22 counteracts G-quadruplex-induced genome instability.

Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.

THSC/TREX-2 deficiency causes replication stress and genome instability in Caenorhabditis elegans.

Transcription is an essential process of DNA metabolism, yet it makes DNA more susceptible to DNA damage. THSC/TREX-2 is a conserved eukaryotic protein complex with a key role in mRNP biogenesis and maturation that prevents genome instability. One source of such instability is linked to transcription, as shown in yeast and human cells, but the underlying mechanism and whether this link is universal is still unclear. To obtain further insight into the putative role of the THSC/TREX-2 complex in genome integrity, we have used Caenorhabditis elegans mutants of the thp-1 and dss-1 components of THSC/TREX-2. These mutants show similar defective meiosis, DNA damage accumulation and activation of the DNA damage checkpoint. However, they differ from each other regarding replication defects, as determined by measuring dUTP incorporation in the germline. Interestingly, this specific thp-1 mutant phenotype can be partially rescued by overexpression of RNase H. Furthermore, both mutants show a mild increase in phosphorylation of histone H3 at Ser10 (H3S10P), a mark previously shown to be linked to DNA-RNA hybrid-mediated genome instability. These data support the view that both THSC/TREX-2 factors prevent transcription-associated DNA damage derived from DNA-RNA hybrid accumulation by separate means.

Harmful R-loops are prevented via different cell cycle-specific mechanisms.

Identifying how R-loops are generated is crucial to know how transcription compromises genome integrity. We show by genome-wide analysis of conditional yeast mutants that the THO transcription complex, prevents R-loop formation in G1 and S-phase, whereas the Sen1 DNA-RNA helicase prevents them only in S-phase. Interestingly, damage accumulates asymmetrically downstream of the replication fork in sen1 cells but symmetrically in the hpr1 THO mutant. Our results indicate that: R-loops form co-transcriptionally independently of DNA replication; that THO is a general and cell-cycle independent safeguard against R-loops, and that Sen1, in contrast to previously believed, is an S-phase-specific R-loop resolvase. These conclusions have important implications for the mechanism of R-loop formation and the role of other factors reported to affect on R-loop homeostasis.

Educational level as a protective factor against the influence of depressive symptoms on cognition in older adults: implications for functional independence during a 10-year follow-up.

OBJECTIVES: To examine whether the educational level moderates the relationship between baseline depressive symptoms and cognitive functioning at 5- and 10-year follow-ups in older adults, considering the association between cognitive functioning and difficulty with activities of daily living (ADL). DESIGN: Using a prospective design, a path analysis was performed. SETTING: In-home, face-to-face interviews and self-administered questionnaires, within the National Social Life, Health, and Aging Project. PARTICIPANTS: In total, 1,461 participants (mean age = 66.62) were followed up from Wave 1 (baseline) to Wave 2 (at 5 years) and Wave 3 (at 10 years). MEASUREMENTS: Depressive symptoms were assessed at baseline. Cognitive functioning and difficulty with ADL were assessed at baseline and at 5 and 10 years. RESULTS: Educational level moderates the relationship between depressive symptoms and cognitive functioning at 5 years (ß = 0.07, SE = 0.03, p = 0.04, Cohen's f2 = 0.02), being depressive symptoms related to poor cognitive functioning only at low educational levels. Cognitive functioning predicts difficulty with ADL at 5 and 10 years (ß = -0.08, SE = 0.03, p = 0.008, Cohen's f2 = 0.01; ß = -0.09, SE = 0.03, p = 0.006, Cohen's f2 = 0.02). The proposed model yielded excellent fit (CFI = 1.00, RMSEA = 0.0001, 90% CI 0.0001-0.03, SRMR = 0.004, and χ2(8) = 7.16, p = 0.52). CONCLUSIONS: Cognitive reserve may act as a protective factor against the effect of depressive symptoms on cognition in older adults, which, in turn, is relevant to their functional independence.

Enhanced N170 to outgroup faces: Perceptual novelty or prejudice?

Habituation to ethnic ingroup members has been reported to be greater than to ethnic outgroup members. This pattern could be due to the lack of perceptive experience (familiarity) with outgroup facial morphs or, alternatively, to the prejudice held toward that outgroup. We explored this disjunctive in 71 participants, all Spanish, who were experimentally habituated to faces from their Ingroup and to faces from two unfamiliar outgroups, one for which there is low probability of prejudice in this population (Non-prejudiced Outgroup), and one for which the probability of prejudice is higher (Prejudiced Outgroup). We indexed habituation through event-related potentials, concretely as the differential amplitude of the face-sensitive N170 component from Initial to Final trials of each group. Afterward, participants completed several prejudice measures. N170 showed significant habituation to all faces, though it did not differ among groups. However, a regression analysis revealed that individual habituation to the Outgroup faces was inversely related to implicit prejudice scores. Importantly, N170 amplitudes were maximal for the Prejudiced Outgroup in both Initial and Final trials. We conclude that these effects are explained by the prejudice held toward a specific outgroup rather than perceptive experience.

Programa de ejercicios físicos terapéuticos para pacientes amputados / Programa de exercícios físicos terapêuticos para pacientes amputados / Therapeutic physical exercises program for amputees

Resumen El proceso de rehabilitación para los pacientes amputados carece de un instrumento metodológico para el desarrollo de la fuerza muscular que les permitan alcanzar mejores niveles de marcha y equilibrio. Por tal motivo, se elaboró un programa de desarrollo de la fuerza muscular dirigido a alcanzar mejores niveles de marcha y equilibrio del paciente amputado. Se analizaron los fundamentos teóricos y metodológicos del tratamiento físico rehabilitador del paciente amputado para establecer el diagnóstico del tratamiento. Asimismo, se determinó la estructura, contenido y metodología del programa, el cual fue valorado por criterio de expertos. El estudio fue de corte descriptivo de naturaleza holística, con un diseño no experimental. La muestra fue de 19 especialistas, seis fisiatras con más de nueve años de experiencia, diez rehabilitadores con más de ocho años de experiencia, un ortopédico y un Doctor en Ciencia de la Cultura Física con más de seis años de experiencia, con una edad promedia de 45 años, presentando un alto dominio y nivel de conocimientos sobre el tema. Los métodos aplicados fueron teóricos y empíricos. Se estructuró el programa de ejercicios físico-terapéuticos para pacientes amputados. Los expertos valoraron de muy adecuado la pertinencia e implementación del programa de ejercicios físico-terapéuticos para pacientes amputados con una efectividad esperada fuerte. Resultó pertinente la confección del programa, ya que justifica la necesidad de orientar científica y metodológicamente a los rehabilitadores físicos.

Resumo O processo de reabilitação de pacientes amputados carece de um instrumento metodológico para o desenvolvimento da força muscular que lhes permita alcançar melhores níveis de marcha e equilíbrio. Por esta razão, foi desenvolvido um programa de desenvolvimento da força muscular para alcançar melhores níveis de marcha e equilíbrio para o paciente amputado. Os fundamentos teóricos e metodológicos do tratamento de reabilitação física do paciente amputado foram analisados para estabelecer o diagnóstico do tratamento. Do mesmo modo, a estrutura, conteúdo e metodologia do programa foram determinados e avaliados por critérios de peritos. O estudo foi descritivo e holístico por natureza, com um desenho não experimental. A amostra foi composta por 19 especialistas, 6 fisiatras com mais de 9 anos de experiência, 10 reabilitadores com mais de 8 anos de experiência, um ortopedista e um Doutor em Ciências da Cultura Física com mais de 6 anos de experiência, com uma idade média de 45 anos, apresentando um elevado nível de domínio e conhecimentos sobre o assunto. Os métodos aplicados eram teóricos e empíricos. O programa de exercícios físico-terapêuticos para pacientes amputados foi estruturado. Os peritos avaliaram a relevância e a implementação do programa de exercícios de fisioterapia para pacientes amputados com uma forte eficácia esperada. A preparação do programa foi pertinente, uma vez que justifica a necessidade de uma orientação científica e metodológica para os profissionais de reabilitação física.

Abstract The rehabilitation process for amputees lacks a methodological instrument for developing muscular strength that allows them to achieve better levels of walking and balance. For this reason, a muscle strength development program was designed to achieve better gait and balance levels for the amputee. The theoretical and methodological foundations of the rehabilitating physical treatment of the amputee patient were analyzed to establish the diagnosis of the treatment. The structure, content and methodology of the program were also determined. Which was valued by expert judgment. The study was descriptive in a holistic nature with a non-experimental design. The sample was of 19 specialists, six physiatrists with more than nine years of experience, ten rehabilitators with more than eight years of experience, an orthopedic and a Doctor of Science in Physical Culture with more than six years of experience, with an average age 45 years old, presenting a domain and level of knowledge on topic four obtained a medium and a high coefficient of 15. The applied methods were theoretical and empirical. The physical-therapeutic exercise program for amputated was structured. The experts rated the relevance and implementation of the physical-therapeutic exercise program for amputees with a strong expected effectiveness as very adequate. The preparation of the program was pertinent, since it justifies the need to guide the physical rehabilitators scientifically and methodologically. Conclusions and recommendations were reached.

Harmful DNA:RNA hybrids are formed in cis and in a Rad51-independent manner.

DNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule produced in cis with its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules produced in trans in a Rad51-mediated reaction. Here, we tested the possibility that such DNA:RNA hybrids constitute a source of recombinogenic DNA damage taking advantage of Rad51-independent single-strand annealing (SSA) assays in the yeast Saccharomyces cerevisiae. For this, we used new constructs designed to induce expression of mRNA transcripts in trans with respect to the SSA system. We show that unscheduled and recombinogenic DNA:RNA hybrids that trigger the SSA event are formed in cis during transcription and in a Rad51-independent manner. We found no evidence that such hybrids form in trans and in a Rad51-dependent manner.

Prejudice drives exogenous attention to outgroups.

Exogenous attention allows the automatic detection of relevant stimuli and the reorientation of our current focus of attention towards them. Faces from an ethnic outgroup tend to capture exogenous attention to a greater extent than faces from an ethnic ingroup. We explored whether prejudice toward the outgroup, rather than lack of familiarity, is driving this effect. Participants (N = 76) performed a digit categorization task while distractor faces were presented. Faces belonged to (i) a prejudiced outgroup, (ii) a non-prejudiced outgroup and (iii) their ingroup. Half of the faces were previously habituated in order to increase their familiarity. Reaction times, accuracy and event-related potentials (ERPs) were recorded to index exogenous attention to distractor faces. Additionally, different indexes of explicit and implicit prejudice were measured, the latter being significantly greater towards prejudiced outgroup. N170 amplitude was greater to prejudiced outgroup-regardless of their habituation status-than to both non-prejudiced outgroup and ingroup faces and was associated with implicit prejudice measures. No effects were observed at the behavioral level. Our results show that implicit prejudice, rather than familiarity, is under the observed attention-related N170 effects and that this ERP component may be more sensitive to prejudice than behavioral measures under certain circumstances.

The DNA damage response acts as a safeguard against harmful DNA-RNA hybrids of different origins.

Despite playing physiological roles in specific situations, DNA-RNA hybrids threat genome integrity. To investigate how cells do counteract spontaneous DNA-RNA hybrids, here we screen an siRNA library covering 240 human DNA damage response (DDR) genes and select siRNAs causing DNA-RNA hybrid accumulation and a significant increase in hybrid-dependent DNA breakage. We identify post-replicative repair and DNA damage checkpoint factors, including those of the ATM/CHK2 and ATR/CHK1 pathways. Thus, spontaneous DNA-RNA hybrids are likely a major source of replication stress, but they can also accumulate and menace genome integrity as a consequence of unrepaired DSBs and post-replicative ssDNA gaps in normal cells. We show that DNA-RNA hybrid accumulation correlates with increased DNA damage and chromatin compaction marks. Our results suggest that different mechanisms can lead to DNA-RNA hybrids with distinct consequences for replication and DNA dynamics at each cell cycle stage and support the conclusion that DNA-RNA hybrids are a common source of spontaneous DNA damage that remains unsolved under a deficient DDR.

Yra1-bound RNA-DNA hybrids cause orientation-independent transcription-replication collisions and telomere instability.

R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA-DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.

Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts.

Conflicts between replication and transcription machineries represent a major source of genomic instability and cells have evolved strategies to prevent such conflicts. However, little is known regarding how cells cope with sudden increases of transcription while replicating. Here, we report the existence of a general mechanism for the protection of genomic integrity upon transcriptional outbursts in S phase that is mediated by Mrc1. The N-terminal phosphorylation of Mrc1 blocked replication and prevented transcription-associated recombination (TAR) and genomic instability during stress-induced gene expression in S phase. An unbiased kinome screening identified several kinases that phosphorylate Mrc1 at the N terminus upon different environmental stresses. Mrc1 function was not restricted to environmental cues but was also required when unscheduled transcription was triggered by low fitness states such as genomic instability or slow growth. Our data indicate that Mrc1 integrates multiple signals, thereby defining a general safeguard mechanism to protect genomic integrity upon transcriptional outbursts.