cellular aging; translation regulation; posttranscriptional modifications; ribosome structure; regulatory ncRNA
GonskikhYulia, GerstlMatthias, KosMartin, BorthNicole, SchossererMarkus, GrillariJohannes, PolacekNorbert (2020), Modulation of mammalian translation by a ribosome-associated tRNA half, in RNA Biology
(2019), Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth, in Nucleic Acids Research
Gonskikh Yulia, Polacek Norbert (2017), Alterations of the translation apparatus during aging and stress response, in Mechanisms of Ageing and Development
, 168, 30-36.
Aging is a complex process characterized by a decline in cellular homeostasis and accumulation of damage that can lead to age-related pathologies. Novel factors and pathways are constantly emerging, but only few are evolutionarily conserved and well understood. One of the few mechanisms involved in the regulation of aging of a wide range of organisms is the reduction of overall protein translation converging on the ribosome. The ribosome has been seen for decades as a static machine that translates mRNAs into proteins. However, over the last few years it became clear that the ribosome is a dynamic structure that responds to various stimuli by adapting its structure, molecular composition, post-translational and post-transcriptional modification status and in consequence its function. Such structurally distinct ribosomes are postulated to be “specialized ribosomes” comprising peculiar functional properties and are thus considered to be engaged in translating specific subsets of cellular messages. We have recently reported that lack of a single, conserved C5 methylation of ribosomal RNA by deletion of the methyltransferase NSUN5 extends the lifespan and stress resistance of yeast, worms and flies. We could show that lack of methylation at ribosomal RNA residue C2278 alters ribosomal structure and thus translational fidelity, resulting in a ‘reprogramming’ of the ribosome towards translation of mRNAs involved in cellular stress-response. With the proof-of-principle that already a single modification of rRNA does alter the life span of organisms, it becomes clear that a systematic analysis of global post-transcriptional modification patterns of rRNA, including pseudouridinylations and base- and sugar methylations, is of crucial importance to understand the changes of the ribosome in terms of synthesis, composition, structure and function in the context of aging and oxidative stress. For such an undertaking the combined expertise of labs in the fields of biogerontology, ribosome structure/function analysis, as well as ribosome biogenesis are necessary and have joined forces within this joint DACH proposal in deepening and further developing of our already successful collaboration on NSUN5.