Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE OF REVIEWSignificant advances have been made in understanding the functional roles of evolutionarily conserved chemical modifications in RNA. By focusing on cytosine-5 methylation, we will ...highlight the latest insight into the mechanisms how posttranscriptional methylation contributes to cell fate decisions, with implications for cancer development.
RECENT FINDINGSSeveral mutations in RNA-modifying enzymes have been identified to cause complex human diseases, and linked posttranscriptional modifications to fundamental cellular processes. Distinct posttranscriptional modifications are implicated in the regulation of stem cell maintenance and cellular differentiation. The dynamic deposition of a methyl mark into noncoding RNAs modulates the adaptive cellular responses to stress and alterations of methylation levels may lead to cancer.
SUMMARYPosttranscriptional modifications such as cytosine-5 methylation are dynamically regulated and may influence tumour development, maintenance, and progression.
This study was designed to estimate the percentage of non-malignant skin tumours (papillomas) progressing to malignant squamous cell carcinomas (SCCs) in a carcinogenesis study using established ...transgenic mouse models. In our skin cancer model, we conditionally induced oncogenic point mutant alleles of p53 and k-ras in undifferentiated, basal cells of the epidermis.
Upon activation of the transgenes through administration of tamoxifen, the vast majority of mice (> 80%) developed skin papillomas, yet primarily around the mouth. Since these tumours hindered the mice eating, they rapidly lost weight and needed to be culled before the papillomas progressed to SCCs. The mouth papillomas formed regardless of the route of application, including intraperitoneal injections, local application to the back skin, or subcutaneous insertion of a tamoxifen pellet. Implantation of a slow releasing tamoxifen pellet into 18 mice consistently led to papilloma formation, of which only one progressed to a malignant SCC. Thus, the challenges for skin carcinogenesis studies using this particular cancer mouse model are low conversion rates of papillomas to SCCs and high frequencies of mouth papilloma formation.
Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) ...TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). However, the mechanisms controlling cTEC and mTEC production from the common TEPC are not understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPCs at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development, and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue
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Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) ...TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). The mechanisms controlling cTEC and mTEC production from the common TEPC are not however understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH-independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPC at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue in vitro and in vivo.
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