The nucleolus, once considered a mere ribosome factory, is now recognized as a dynamic hub influencing nearly every aspect of cellular life, from genome organization to stress response and ageing. Despite being a hallmark of eukaryotic cells, recent discoveries reveal that even prokaryotes exhibit nucleolus-like structures, hinting at ancient origins for nucleolar functions. This review explores the evolutionary journey of the nucleolus, tracing its roots back to early life and examining its structural and functional diversity across domains. We highlight key nucleolar proteins that play vital roles not only in ribosome production but also in regulating cell cycle, DNA repair and cellular stress, linking nucleolar activity directly to health and disease. Dysfunctions in nucleolar processes are implicated in cancer, ribosomopathies and neurodegenerative disorders, positioning the nucleolus as a critical target for innovative therapeutic strategies. As advanced imaging and molecular techniques unlock deeper insights into both canonical and mysterious non-canonical roles, the nucleolus stands as a model for how cellular microenvironments can evolve to meet complex biological demands. By addressing open questions surrounding the evolution of the nucleolus, its organization and diverse functions, the ideas presented here aim to contribute to the ongoing discussion, challenging traditional paradigms and suggesting new avenues for uncovering the fundamental principles that drive cellular life.

The catalytic, regulatory and structural properties of RNA, combined with their extraordinary ubiquity in cellular processes, are consistent with the proposal that this molecule played a much more conspicuous role in heredity and metabolism during the early stages of biological evolution. This review explores the pivotal role of RNA in the earliest life forms and its relevance in modern biological systems. It examines current models that study the early evolution of life, providing insights into the primordial RNA world and its legacy in contemporary biology.

Low complexity regions (LCRs) are protein sequences formed by a set of compositionally biased residues. LCRs are extremely abundant in cellular proteins and have also been reported in viruses, where they may partake in evasion of the host immune system. Analyses of 28,231 SARS-CoV-2 whole proteomes and of 261,051 spike protein sequences revealed the presence of four extremely conserved LCRs in the spike protein of several SARS-CoV-2 variants. With the exception of Iota, where it is absent, the Spike LCR-1 is present in the signal peptide of 80.57% of the Delta variant sequences, and in other variants of concern and interest. The Spike LCR-2 is highly prevalent (79.87%) in Iota. Two distinctive LCRs are present in the Delta spike protein. The Delta Spike LCR-3 is present in 99.19% of the analyzed sequences, and the Delta Spike LCR-4 in 98.3% of the same set of proteins. These two LCRs are located in the furin cleavage site and HR1 domain, respectively, and may be considered hallmark traits of the Delta variant. The presence of the medically-important point mutations P681R and D950N in these LCRs, combined with the ubiquity of these regions in the highly contagious Delta variant opens the possibility that they may play a role in its rapid spread.

Nidoviruses and arenaviruses are the only known RNA viruses encoding a 3'-5' exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19.