RESUMO
Ribosome biogenesis (RiBi) is one of the most complex and energy demanding processes in human cells, critical for cell growth and proliferation. Strong causal links between inherited and acquired impairment in RiBi with cancer pathogenesis are emerging, pointing to RiBi as an attractive therapeutic target for cancer. Here, we will highlight new knowledge about causes of excessive or impaired RiBi and the impact of these changes on protein synthesis. We will also discuss how new knowledge about secondary consequences of dysregulated RiBi and protein synthesis, including proteotoxic stress, metabolic alterations, adaptive transcriptional and translational programs, and the impaired ribosome biogenesis checkpoint (IRBC) provide a foundation for the development of new anticancer therapies.
Assuntos
Benzotiazóis/farmacologia , Carcinogênese/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , RNA Polimerase I/antagonistas & inibidores , Ribossomos/metabolismo , Benzotiazóis/uso terapêutico , Carcinogênese/genética , Carcinogênese/patologia , Reparo do DNA/genética , Humanos , Mutação , Naftiridinas/uso terapêutico , Neoplasias/genética , Neoplasias/patologia , Biogênese de Organelas , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Polimerase I/metabolismo , Proteínas Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Mutações Sintéticas Letais , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação/efeitos dos fármacosRESUMO
The European cave salamander Proteus anguinus is a charismatic amphibian endemic to the concealed and inaccessible subterranean waters of the Dinaric Karst. Despite its exceptional conservation importance not much is known about its ecology and interactions with the groundwater microbiome. The cutaneous microbiota of amphibians is an important driver of metabolic capabilities and immunity, and thus a key factor in their wellbeing and survival. We used high-throughput 16S rRNA gene sequencing based on seven variable regions to examine the bacteriome of the skin of five distinct evolutionary lineages of P. anguinus and in their groundwater environment. The skin bacteriomes turned out to be strongly filtered subsamples of the environmental microbial community. The resident microbiota of the analyzed individuals was dominated by five bacterial taxa. Despite an indicated functional redundancy, the cutaneous bacteriome of P. anguinus presumably provides protection against invading microbes by occupying the niche, and thus could serve as an indicator of health status. Besides conservation implications for P. anguinus, our results provide a baseline for future studies on other endangered neotenic salamanders.