The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate ...pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.
•
Identification of critical genes regulating p53 via nucleolar surveillance pathway (NSP)
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When disrupted, genes associated with ribosome biogenesis most potently stabilize p53
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A functional NSP is essential for all nuclear-acting stresses to stabilize p53
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The NSP ensures that ribosome biogenesis is synchronized with cellular proliferation
Hannan et al. utilize genome-wide functional screening approaches to identify genes and pathways that, when perturbed, modulate p53 under ribosomal stress, including HEATR3. Their findings demonstrate that the nucleolar surveillance pathway is a primary integrator of all nuclear-acting stresses that stabilize p53.
Export of protein-coding and non-coding RNA molecules from the nucleus to the cytoplasm is critical for gene expression. This necessitates the continuous transport of RNA species of different size, ...shape and function through nuclear pore complexes via export receptors and adaptor proteins. Here, we provide an overview of the major RNA export pathways in humans, highlighting the similarities and differences between each. Its importance is underscored by the growing appreciation that deregulation of RNA export pathways is associated with human diseases like cancer.
Nuclear export of circular RNA Ngo, Linh H; Bert, Andrew G; Dredge, B Kate ...
Nature (London),
03/2024, Letnik:
627, Številka:
8002
Journal Article
Recenzirano
Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells
, are formed by back-splicing of precursor mRNAs in the nucleus
. circRNAs ...are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.
Forum papers are thought-provoking opinion pieces or essays founded in fact, sometimes containing speculation, on a civil engineering topic of general interest and relevance to the readership of the ...journal. The views expressed in this Forum article do not necessarily reflect the views of ASCE or the Editorial Board of the journal.
Gaining insights into local people’s views, values and preferences for different conservation management options are increasingly gaining importance among conservationists and decision-makers. This ...can be achieved through the assessment and understanding of conservation attitudes and perceptions of rural communities including demographic characteristics predicting the attitudes to design and implement conservation policies in a more socially acceptable manner. In this study, we developed and validated user-friendly indices to measure attitudes towards the African elephant, a flagship species and its conservation in Trans Mara District. An iterative item reliability analysis was executed on household data from a random sample of 367 respondents using Cronbach’s Alpha in SPSS. Results yielded two indices; (i) Elephant Attitude Index (EAI); and (ii) Maasai Mara National Reserve Attitude Index (MAI). The EAI had a Cronbach’s Alpha coefficient of 0.73 while the MAI had a Cronbach’s Alpha coefficient of 0.77. Data analysis revealed that (i) location of residence; (ii) age of respondent; (iii) number of income sources; (iv) gender of the respondent; and (v) benefit reception were the main determinants of EAI and MAI in TM. Our attitude indices can assist conservation practitioners and decision-makers to prioritise resources, on the assumption that high-scoring individuals are more likely to participate in conservation initiatives. We encourage making available different sources of income for residents and working towards improving the involvement of younger people and women in conservation activities in TM.
Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative ...crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations
. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.
Abstract
We present JWST NIRCam nine-band near-infrared imaging of the luminous
z
= 10.6 galaxy GN-z11 from the JWST Advanced Deep Extragalactic Survey of the GOODS-N field. We find a spectral energy ...distribution (SED) entirely consistent with the expected form of a high-redshift galaxy: a clear blue continuum from 1.5 to 4
μ
m with a complete dropout in F115W. The core of GN-z11 is extremely compact in JWST imaging. We analyze the image with a two-component model, using a point source and a Sérsic profile that fits to a half-light radius of 200 pc and an index
n
= 0.9. We find a low-surface-brightness haze about 0.″4 to the northeast of the galaxy, which is most likely a foreground object but might be a more extended component of GN-z11. At a spectroscopic redshift of 10.60 (Bunker et al. 2023), the comparison of the NIRCam F410M and F444W images spans the Balmer jump. From population-synthesis modeling, here assuming no light from an active galactic nucleus, we reproduce the SED of GN-z11, finding a stellar mass of ∼10
9
M
⊙
, a star formation rate of ∼20
M
⊙
yr
−1
, and a young stellar age of ∼20 Myr. Since massive galaxies at high redshift are likely to be highly clustered, we search for faint neighbors of GN-z11, finding nine galaxies out to ∼5 comoving Mpc transverse with photometric redshifts consistent with
z
= 10.6, and a tenth more tentative dropout only 3″ away. This is consistent with GN-z11 being hosted by a massive dark-matter halo (≈8 × 10
10
M
⊙
), though lower halo masses cannot be ruled out.
Human-elephant conflict is an often intractable problem that threatens the contribution of conservation interventions to human wellbeing and securing livelihoods in Africa and Asia. Local human ...populations living in key elephant ranges are among the world's most poor and vulnerable people. In efforts to address this problem, previous studies have mainly focused on the direct impacts of conflict and applied standard regression models based on the assumption of individual-level homogeneity. More recently, human-elephant conflict has been seen to extend well beyond the physical, to the psychological and social sides of wellbeing. However, the impacts on human wellbeing have not been robustly explored, especially for local communities co-existing with elephants. We evaluated the impacts of conflicts on the wellbeing of local communities around the world-famous Masai Mara National Reserve in Kenya. We conducted 18 focus group discussions with 120 community members in different locations and administered a questionnaire survey to 367 sampled households from 26 sub-locations in Trans Mara. We used descriptive statistics with appropriate statistical tests, including propensity score matching, to evaluate the impacts of conflict on human wellbeing. Before matching, the results of the descriptive statistics showed differences between households experiencing conflicts and those without in terms of gender, age, education level, household size, benefiting from elephant conservation, main occupation and number of income sources. Our matching results indicate the existence of a significant negative and positive impacts on four and one of our eight wellbeing indicators for households that experienced conflicts, respectively. Better conflict mitigation approaches and conservation policies need to be adopted to realize the harmonious and concurrent development of ecological and wellbeing objectives.
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