Influence of cell volume on the gene transcription rate.

Cells vary in volume throughout their life cycle and in many other circumstances, while their genome remains identical. Hence, the RNA production factory must adapt to changing needs, while maintaining the same production lines. This paradox is resolved by different mechanisms in distinct cells and circumstances. RNA polymerases have evolved to cope with the particular circumstances of each case and the different characteristics of the several RNA molecule types, especially their stabilities. Here we review current knowledge on these issues. We focus on the yeast Saccharomyces cerevisiae, where many of the studies have been performed, although we compare and discuss the results obtained in other eukaryotes and propose several ideas and questions to be tested and solved in the future. TAKE AWAY.

The association of the RSC remodeler complex with chromatin is influenced by the prefoldin-like Bud27 and determines nucleosome positioning and polyadenylation sites usage in Saccharomyces cerevisiae.

The tripartite interaction between the chromatin remodeler complex RSC, RNA polymerase subunit Rpb5 and prefoldin-like Bud27 is necessary for proper RNA pol II elongation. Indeed lack of Bud27 alters this association and affects transcription elongation. This work investigates the consequences of lack of Bud27 on the chromatin association of RSC and RNA pol II, and on nucleosome positioning. Our results demonstrate that RSC binds chromatin in gene bodies and lack of Bud27 alters this association, mainly around polyA sites. This alteration impacts chromatin organization and leads to the accumulation of RNA pol II molecules around polyA sites, likely due to pausing or arrest. Our data suggest that RSC is necessary to maintain chromatin organization around those sites, and any alteration of this organization results in the widespread use of alternative polyA sites. Finally, we also find a similar molecular phenotype that occurs upon TOR inhibition with rapamycin, which suggests that alternative polyadenylation observed upon TOR inhibition is likely Bud27-dependent.

Enhanced gene regulation by cooperation between mRNA decay and gene transcription.

It has become increasingly clear in the last few years that gene expression in eukaryotes is not a linear process from mRNA synthesis in the nucleus to translation and degradation in the cytoplasm, but works as a circular one where the mRNA level is controlled by crosstalk between nuclear transcription and cytoplasmic decay pathways. One of the consequences of this crosstalk is the approximately constant level of mRNA. This is called mRNA buffering and happens when transcription and mRNA degradation act at compensatory rates. However, if transcription and mRNA degradation act additively, enhanced gene expression regulation occurs. In this work, we analyzed new and previously published genomic datasets obtained for several yeast mutants related to either transcription or mRNA decay that are not known to play any role in the other process. We show that some, which were presumed only transcription factors (Sfp1) or only decay factors (Puf3, Upf2/3), may represent examples of RNA-binding proteins (RBPs) that make specific crosstalk to enhance the control of the mRNA levels of their target genes by combining additive effects on transcription and mRNA stability. These results were mathematically modeled to see the effects of RBPs when they have positive or negative effects on mRNA synthesis and decay rates. We found that RBPs can be an efficient way to buffer or enhance gene expression responses depending on their respective effects on transcription and mRNA stability.

High Plasma Levels of Fibroblast Growth Factor 23 Are Associated with Increased Risk of COVID-19 in End-Stage Renal Disease Patients on Hemodialysis: Results of a Prospective Cohort.

End-stage renal disease (ESRD) patients are a population with high rates of COVID-19 and mortality. These patients present a low response to anti-SARS-CoV-2 immunization, which is associated with immune dysfunction. ESRD patients also present high plasma titers of Fibroblast Growth Factor 23 (FGF23), a protein hormone that reduces immune response in vivo and in vitro. Increased FGF23 levels associate with higher infection-related hospitalizations and adverse infectious outcomes. Thus, we evaluated whether ESRD patients with high FGF23 titers have an increased rate of SARS-CoV-2 infection. METHODS: We performed a prospective cohort of ESRD patients in hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19 infections, hospitalizations, and mortality between January 2020 and December 2021. RESULTS: We evaluated 243 patients. Age: 60.4 ± 10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus 9.9%; Hazard ratio: 1.92 [1.03-3.56], p = 0.039). Multivariate analysis showed that increased plasma FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. DISCUSSION: Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a factor implicated in the association with worse clinical outcomes. Further data are needed to confirm this hypothesis.

Toward an Intelligent Campus: IoT Platform for Remote Monitoring and Control of Smart Buildings.

With the growing need to obtain information about power consumption in buildings, it is necessary to investigate how to collect, store, and visualize such information using low-cost solutions. Currently, the available building management solutions are expensive and challenging to support small and medium-sized buildings. Unfortunately, not all buildings are intelligent, making it difficult to obtain such data from energy measurement devices and appliances or access such information. The internet of things (IoT) opens new opportunities to support real-time monitoring and control to achieve future smart buildings. This work proposes an IoT platform for remote monitoring and control of smart buildings, which consists of four-layer architecture: power layer, data acquisition layer, communication network layer, and application layer. The proposed platform allows data collection for energy consumption, data storage, and visualization. Various sensor nodes and measurement devices are considered to collect information on energy use from different building spaces. The proposed solution has been designed, implemented, and tested on a university campus considering three scenarios: an office, a classroom, and a laboratory. This work provides a guideline for future implementation of intelligent buildings using low-cost open-source solutions to enable building automation, minimize power consumption costs, and guarantee end-user comfort.

Nucleo-cytoplasmic shuttling of RNA-binding factors: mRNA buffering and beyond.

Gene expression is a highly regulated process that adapts RNAs and proteins content to the cellular context. Under steady-state conditions, mRNA homeostasis is robustly maintained by tight controls that act on both nuclear transcription and cytoplasmic mRNA stability. In recent years, it has been revealed that several RNA-binding proteins (RBPs) that perform functions in mRNA decay can move to the nucleus and regulate transcription. The RBPs involved in transcription can also travel to the cytoplasm and regulate mRNA degradation and/or translation. The multifaceted functions of these shuttling nucleo-cytoplasm RBPs have raised the possibility that they can act as mRNA metabolism coordinators. In addition, this indicates the existence of crosstalk mechanisms between the enzymatic machineries that drive the different mRNA life-cycle phases. The buffering of the mRNA concentration is the best known consequence of a transcription-degradation crosstalk counteraction, but alternative ways of RBP action can also imply enhanced gene regulation.

Proteinosis alveolar pulmonar: reporte de caso en paciente con linfoma no hodgkin mesentérico / Pulmonary alveolar proteinosis: report of a case in patient with history of mesenteric non-hodgkin lymphoma

Objetivos: Exponer en base a un caso clínico una revisión de literatura reciente sobre Proteinosis alveolar pulmonar (PAP). Presentación del caso: Revisión de ficha clínica electrónica de paciente de sexo masculino de 76 años con antecedente de linfoma no Hodgkin (LNH) mesentérico, estirpe B de tipo folicular, quien acude en forma reiterada a servicios de urgencia por cuadro de dos meses de evolución de fiebre, compromiso del estado general y tos. Al examen físico destaca crépitos en hemitórax derecho. Se realizó Tomografía computada (TC) de tórax que mostró opacidades pulmonares en vidrio esmerilado periféricas, con engrosamiento septal liso y algunas bandas retráctiles subpleurales. Se manejó ambulatoriamente con Azitromicina por una semana. Sin respuesta, evoluciona con baja de peso y diaforesis nocturna. Nueva TC de tórax en enero 2021, muestra nuevos focos de "empedrado" periféricos extensos, descrito como "crazy paving", focos de vidrio esmerilado difusos extensos, sin condensación y con resolución de bandas retráctiles. Estudio infeccioso negativo. Se realiza lavado broncoalveolar (LBA) con estudio histológico de líquido que muestra proceso inflamatorio crónico con abundantes macrófagos y material proteináceo. Discusión: Tras el descarte de patología infecciosa, se orientó el estudio hacia otras causas de enfermedad parenquimatosa pulmonar. Así, resulta fundamental la descripción correcta del patrón imagenológico tomográfico y el LBA que resultaron compatibles con PAP. Conclusión: La PAP es una patología infrecuente, pero una historia clínica adecuada, el planteamiento de diagnósticos diferenciales de neumonía de lenta resolución, asociado el reconocimiento del patrón radiológico característico y el estudio histológico con LBA permiten realizar un diagnóstico certero, con gran implicancia terapéutica.

Objective: To present a review of recent literature on pulmonary alveolar proteinosis (PAP) based on a clinical case. Presentation of the case: Review of electronic clinical record of a 76 years-old masculine patient with history of mesenteric Non-Hodgkin Lymphoma (NHL) follicular-type lineage B, who repeatedly attended the emergency services due to a two-month history of symptoms of fever, compromised general condition and cough. Physical examination revealed crepitus in the right hemithorax. Chest computed tomography (CT) was performed, which showed peripheral ground-glass pulmonary opacities, with smooth septal thickening and some subpleural retractile bands. He was managed on an outpatient basis with Azithromycin for one week. No response; evolves with weight loss and night diaphoresis. New chest CT in January 2021, shows new extensive peripheral "cobblestone" foci, described as "crazy paving", extensive diffuse ground glass foci, without condensation and with resolution of retractile bands. Negative infectious study. Bronchoalveolar lavage (BAL) was performed with a histological study of the fluid showing a chronic inflammatory process with abundant macrophages and proteinaceous material. Discussion: After ruling out infectious pathology, the study was oriented towards other causes of pulmonary parenchymal disease. Thus, the correct description of the tomographic imaging pattern and the BAL that were compatible with PAP are essential. Conclusion: PAP is an infrequent pathology, but an adequate clinical history, the approach to differential diagnoses of slowly resolving pneumonia, associated with the recognition of the characteristic radiological pattern and the histological study with BAL allow an accurate diagnosis to be made, with great therapeutic implications.

Clinical characteristics and in-hospital mortality of patients with COVID-19 in Chile: A prospective cohort study.

AIMS OF THIS STUDY: To describe the Latin American population affected by COVID-19, and to determine relevant risk factors for in-hospital mortality. METHODS: We prospectively registered relevant clinical, laboratory, and radiological data of adult patients with COVID-19, admitted within the first 100 days of the pandemic from a single teaching hospital in Santiago, Chile. The primary outcome was in-hospital mortality. Secondary outcomes included the need for respiratory support and pharmacological treatment, among others. We combined the chronic disease burden and the severity of illness at admission with predefined clinically relevant risk factors. Cox regression models were used to identify risk factors for in-hospital mortality. RESULTS: We enrolled 395 adult patients, their median age was 61 years; 62.8% of patients were male and 40.1% had a Modified Charlson Comorbidity Index (MCCI) ≥5. Their median Sequential Organ Failure Assessment (SOFA) score was 3; 34.9% used a high-flow nasal cannula and 17.5% required invasive mechanical ventilation. The in-hospital mortality rate was 14.7%. In the multivariate analysis, were significant risk factors for in-hospital mortality: MCCI ≥5 (HR 4.39, P < .001), PaO2 /FiO2 ratio ≤200 (HR 1.92, P = .037), and advanced chronic respiratory disease (HR 3.24, P = .001); pre-specified combinations of these risk factors in four categories was associated with the outcome in a graded manner. CONCLUSIONS AND CLINICAL IMPLICATIONS: The relationship between multiple prognostic factors has been scarcely reported in Latin American patients with COVID-19. By combining different clinically relevant risk factors, we can identify COVID-19 patients with high-, medium- and low-risk of in-hospital mortality.

Acute liver failure due to herpes simplex virus: diagnostic clues and potential role of plasmapheresis: A case report.

INTRODUCTION: Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported. PATIENT CONCERNS: A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function. DIAGNOSIS: ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood. INTERVENTIONS: Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated. OUTCOMES: After 6 cycles of plasmapheresis and supportive care, the patient's condition improved without undergoing liver transplantation. CONCLUSIONS: ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered.

Transcriptional Run-on: Measuring Nascent Transcription at Specific Genomic Sites in Yeast.

DNA transcription by RNA polymerases has always interested the scientific community as it is one of the most important processes involved in genome expression. This has led scientists to come up with different protocols allowing analysis of this process in specific locations across the genome by quantitating the amount of RNA polymerases transcribing that genomic site in a cell population. This can be achieved by either detecting the total number of polymerases in contact with that region (i.e., by chromatin immunoprecipitation (ChIP) with anti-RNA polymerase antibodies) or by measuring the number of polymerases that are effectively engaged in transcription in that position. This latter strategy is followed using transcription run-on (TRO), also known as nuclear run-on (NRO), which was first developed in mammalian cells over 40 years ago and has since been adapted to many other different organisms and high-throughput methods. Here, we detail the procedure for performing TRO in Saccharomyces cerevisiae for single genomic regions to study active transcription on a single gene scale. To do so, we wash the cells in the detergent sarkosyl, which prevents new initiations at the promoter level, and then perform an in situ reaction, leading to the radiolabeling of transcripts by RNA polymerases that were already engaged in transcription at the moment of harvesting. By subsequently quantitating the signal of these transcripts, we can determine the level of active transcription in a single gene. This presents a major advantage over other forms of transcription quantitation such as RNA polymerase ChIP, since in the latter, both active and inactive polymerases are measured. By combining both ChIP and TRO, the amount of inactive or paused polymerases on a particular gene can be estimated. Graphic abstract: Transcriptional run-on scheme.

The total mRNA concentration buffering system in yeast is global rather than gene-specific.

Gene expression in eukaryotes does not follow a linear process from transcription to translation and mRNA degradation. Instead it follows a circular process in which cytoplasmic mRNA decay crosstalks with nuclear transcription. In many instances, this crosstalk contributes to buffer mRNA at a roughly constant concentration. Whether the mRNA buffering concept operates on the total mRNA concentration or at the gene-specific level, and if the mechanism to do so is a global or a specific one, remain unknown. Here we assessed changes in mRNA concentrations and their synthesis rates along the transcriptome of aneuploid strains of the yeast Saccharomyces cerevisiae We also assessed mRNA concentrations and their synthesis rates in nonsense-mediated decay (NMD) targets in euploid strains. We found that the altered synthesis rates in the genes from the aneuploid chromosome and the changes in their mRNA stabilities were not counterbalanced. In addition, the stability of NMD targets was not specifically compensated by the changes in synthesis rate. We conclude that there is no genetic compensation of NMD mRNA targets in yeast, and total mRNA buffering uses mostly a global system rather than a gene-specific one.

Human prefoldin modulates co-transcriptional pre-mRNA splicing.

Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the co-translational folding of actin and tubulin monomers. Additional functions of prefoldin have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin perturbations provoked transcriptional alterations across the human genome. Severe pre-mRNA splicing defects were also detected, particularly after serum stimulation. We found impairment of co-transcriptional splicing during transcription elongation, which explains why the induction of long genes with a high number of introns was affected the most. We detected genome-wide prefoldin binding to transcribed genes and found that it correlated with the negative impact of prefoldin depletion on gene expression. Lack of prefoldin caused global decrease in Ser2 and Ser5 phosphorylation of the RNA polymerase II carboxy-terminal domain. It also reduced the recruitment of the CTD kinase CDK9 to transcribed genes, and the association of splicing factors PRP19 and U2AF65 to chromatin, which is known to depend on CTD phosphorylation. Altogether the reported results indicate that human prefoldin is able to act locally on the genome to modulate gene expression by influencing phosphorylation of elongating RNA polymerase II, and thereby regulating co-transcriptional splicing.

Cell volume homeostatically controls the rDNA repeat copy number and rRNA synthesis rate in yeast.

The adjustment of transcription and translation rates to the changing needs of cells is of utmost importance for their fitness and survival. We have previously shown that the global transcription rate for RNA polymerase II in budding yeast Saccharomyces cerevisiae is regulated in relation to cell volume. Total mRNA concentration is constant with cell volume since global RNApol II-dependent nascent transcription rate (nTR) also keeps constant but mRNA stability increases with cell size. In this paper, we focus on the case of rRNA and RNA polymerase I. Contrarily to that found for RNA pol II, we detected that RNA polymerase I nTR increases proportionally to genome copies and cell size in polyploid cells. In haploid mutant cells with larger cell sizes, the rDNA repeat copy number rises. By combining mathematical modeling and experimental work with the large-size cln3 strain, we observed that the increasing repeat copy number is based on a feedback mechanism in which Sir2 histone deacetylase homeostatically controls the amplification of rDNA repeats in a volume-dependent manner. This amplification is paralleled with an increase in rRNA nTR, which indicates a control of the RNA pol I synthesis rate by cell volume.

Xrn1 influence on gene transcription results from the combination of general effects on elongating RNA pol II and gene-specific chromatin configuration.

mRNA homoeostasis is favoured by crosstalk between transcription and degradation machineries. Both the Ccr4-Not and the Xrn1-decaysome complexes have been described to influence transcription. While Ccr4-Not has been shown to directly stimulate transcription elongation, the information available on how Xrn1 influences transcription is scarce and contradictory. In this study we have addressed this issue by mapping RNA polymerase II (RNA pol II) at high resolution, using CRAC and BioGRO-seq techniques in Saccharomyces cerevisiae. We found significant effects of Xrn1 perturbation on RNA pol II profiles across the genome. RNA pol II profiles at 5' exhibited significant alterations that were compatible with decreased elongation rates in the absence of Xrn1. Nucleosome mapping detected altered chromatin configuration in the gene bodies. We also detected accumulation of RNA pol II shortly upstream of polyadenylation sites by CRAC, although not by BioGRO-seq, suggesting higher frequency of backtracking before pre-mRNA cleavage. This phenomenon was particularly linked to genes with poorly positioned nucleosomes at this position. Accumulation of RNA pol II at 3' was also detected in other mRNA decay mutants. According to these and other pieces of evidence, Xrn1 seems to influence transcription elongation at least in two ways: by directly favouring elongation rates and by a more general mechanism that connects mRNA decay to late elongation.

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer.

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial-mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. First, the mRNA expression of 518 non-small cell LC (NSCLC) cases from The Cancer Genome Atlas (TCGA) database was evaluated. Patients with PFDN1 overexpression had lower overall survival (OS; 45 vs. 86 months; p = 0.034). We then assessed the impact of PFDN expression on outcome in 58 NSCLC patients with available tumor tissue samples. PFDN1, 3, and 5 overexpression were found in 38% (n = 22), 53% (n = 31), and 41% (n = 24) of tumor samples. PFDN1, 3, and 5 overexpression were significantly associated with lower OS, lower disease-free survival (DFS), and lower distant metastasis-free survival (DMFS) for PFDN1 and 3 with a trend for PFDN5. In multivariate analysis, PFDN5 retained significance for OS (hazard ratio (HR) 2.56; p = 0.007) and PFDN1 for DFS (HR 2.53; p = 0.010) and marginally for DMFS (HR 2.32; p = 0.053). Our results indicate that protein response markers, such as PFDN1, 3, and 5, may complement mRNA signatures and be useful for determining the most appropriate therapy for NSCLC patients.

The mRNA degradation factor Xrn1 regulates transcription elongation in parallel to Ccr4.

Co-transcriptional imprinting of mRNA by Rpb4 and Rpb7 subunits of RNA polymerase II (RNAPII) and by the Ccr4-Not complex conditions its post-transcriptional fate. In turn, mRNA degradation factors like Xrn1 are able to influence RNAPII-dependent transcription, making a feedback loop that contributes to mRNA homeostasis. In this work, we have used repressible yeast GAL genes to perform accurate measurements of transcription and mRNA degradation in a set of mutants. This genetic analysis uncovered a link from mRNA decay to transcription elongation. We combined this experimental approach with computational multi-agent modelling and tested different possibilities of Xrn1 and Ccr4 action in gene transcription. This double strategy brought us to conclude that both Xrn1-decaysome and Ccr4-Not regulate RNAPII elongation, and that they do it in parallel. We validated this conclusion measuring TFIIS genome-wide recruitment to elongating RNAPII. We found that xrn1Δ and ccr4Δ exhibited very different patterns of TFIIS versus RNAPII occupancy, which confirmed their distinct role in controlling transcription elongation. We also found that the relative influence of Xrn1 and Ccr4 is different in the genes encoding ribosomal proteins as compared to the rest of the genome.

Homeostasis in the Central Dogma of molecular biology: the importance of mRNA instability.

Cell survival requires the control of biomolecule concentration, i.e. biomolecules should approach homeostasis. With information-carrying macromolecules, the particular concentration variation ranges depend on each type: DNA is not buffered, but mRNA and protein concentrations are homeostatically controlled, which leads to the ribostasis and proteostasis concepts. In recent years, we have studied the particular features of mRNA ribostasis and proteostasis in the model organism S. cerevisiae. Here we extend this study by comparing published data from three other model organisms: E. coli, S. pombe and cultured human cells. We describe how mRNA ribostasis is less strict than proteostasis. A constant ratio appears between the average decay and dilution rates during cell growth for mRNA, but not for proteins. We postulate that this is due to a trade-off between the cost of synthesis and the response capacity. This compromise takes place at the transcription level, but is not possible at the translation level as the high stability of proteins, versus that of mRNAs, precludes it. We hypothesize that the middle-place role of mRNA in the Central Dogma of Molecular Biology and its chemical instability make it more suitable than proteins for the fast changes needed for gene regulation.

Functional Contributions of Prefoldin to Gene Expression.

Prefoldin is a co-chaperone that evolutionarily originates in archaea, is universally present in all eukaryotes and acts as a co-chaperone by facilitating the supply of unfolded or partially folded substrates to class II chaperonins. Eukaryotic prefoldin is known mainly for its functional relevance in the cytoplasmic folding of actin and tubulin monomers during cytoskeleton assembly. However, the role of prefoldin in chaperonin-mediated folding is not restricted to cytoskeleton components, but extends to both the assembly of other cytoplasmic complexes and the maintenance of functional proteins by avoiding protein aggregation and facilitating proteolytic degradation. Evolution has favoured the diversification of prefoldin subunits, and has allowed the so-called prefoldin-like complex, with specialised functions, to appear. Subunits of both canonical and prefoldin-like complexes have also been found in the nucleus of yeast and metazoan cells, where they have been functionally connected with different gene expression steps. Plant prefoldin has also been detected in the nucleus and is physically associated with a gene regulator. Here we summarise information available on the functional involvement of prefoldin in gene expression, and discuss the implications of these results for the relationship between prefoldin structure and function.

High levels of histones promote whole-genome-duplications and trigger a Swe1WEE1-dependent phosphorylation of Cdc28CDK1.

Whole-genome duplications (WGDs) have played a central role in the evolution of genomes and constitute an important source of genome instability in cancer. Here, we show in Saccharomyces cerevisiae that abnormal accumulations of histones are sufficient to induce WGDs. Our results link these WGDs to a reduced incorporation of the histone variant H2A.Z to chromatin. Moreover, we show that high levels of histones promote Swe1WEE1 stabilisation thereby triggering the phosphorylation and inhibition of Cdc28CDK1 through a mechanism different of the canonical DNA damage response. Our results link high levels of histones to a specific type of genome instability that is quite frequently observed in cancer and uncovers a new mechanism that might be able to respond to high levels of histones.

Feedback regulation of ribosome assembly.

Ribosome biogenesis is a crucial process for growth and constitutes the major consumer of cellular resources. This pathway is subjected to very stringent regulation to ensure correct ribosome manufacture with a wide variety of environmental and metabolic changes, and intracellular insults. Here we summarise our current knowledge on the regulation of ribosome biogenesis in Saccharomyces cerevisiae by particularly focusing on the feedback mechanisms that maintain ribosome homeostasis. Ribosome biogenesis in yeast is controlled mainly at the level of the production of both pre-rRNAs and ribosomal proteins through the transcriptional and post-transcriptional control of the TORC1 and protein kinase A signalling pathways. Pre-rRNA processing can occur before or after the 35S pre-rRNA transcript is completed; the switch between these two alternatives is regulated by growth conditions. The expression of both ribosomal proteins and the large family of transacting factors involved in ribosome biogenesis is co-regulated. Recently, it has been shown that the synthesis of rRNA and ribosomal proteins, but not of trans-factors, is coupled. Thus the so-called CURI complex sequesters specific transcription factor Ifh1 to repress ribosomal protein genes when rRNA transcription is impaired. We recently found that an analogue system should operate to control the expression of transacting factor genes in response to actual ribosome assembly performance. Regulation of ribosome biogenesis manages situations of imbalanced ribosome production or misassembled ribosomal precursors and subunits, which have been closely linked to distinct human diseases.