Reviews & Analysis

Recent studies have provided novel insight into the biogenesis of long non-coding RNAs (lncRNAs) and their specific functions. The functions of lncRNAs vary from transcriptional and post-transcriptional gene regulation to the assembly and function of membraneless nuclear bodies, and are relevant to neuronal disorders, immune responses and cancer.

Nicotinamide adenine dinucleotide (NAD⁺) is a central redox factor and enzymatic cofactor that functions in a plethora of cellular processes, including metabolic pathways and DNA metabolism, and affects cell fate and function. NAD⁺ levels gradually decline with age, and therapeutic elevation of NAD⁺ levels is being trialled for extending human healthspan and lifespan.

Cellular senescence is characterized by a permanent proliferation arrest and the establishment of a senescence-associated secretory phenotype. This Review discusses the mechanisms of cellular senescence and induction of a senescence-associated secretory phenotype, recent insights into how senescence contributes to ageing, and the potential of senolytic and senomorphic therapies in ageing and associated diseases.

Transcript elongation by RNA polymerase II can be perturbed by barriers such as promoter-proximal pausing and nucleosomes and by obstacles such as the replication machinery and DNA lesions. Recent studies revealed how different contexts of RNA polymerase II stalling are distinguished and resolved, and how unresolved stalling can cause genome instability.

Mechanical forces are important regulators of cell function and behaviour. This role is partly achieved through the modulation of cell metabolism, which, reciprocally, affects tissue mechanics. Unravelling the mechanisms of this crosstalk will increase our understanding of how cells interact with their microenvironment.

The mitochondrial proteome comprises ~1,000–1,500 nuclear-encoded and mitochondrial-encoded proteins. To ensure proper mitochondrial function, cells use multiple mechanisms of quality control that survey mitochondrial protein biogenesis, import and folding, and allow mitochondria to adapt to the changing needs as well as to respond to stresses that compromise proteostasis.

Various physiological processes including development and maintenance of epithelia, cell–cell fusion, neuronal function and immune responses rely on the establishment of direct cell–cell contacts. Despite their diversity, the different cell–cell interfaces can be viewed as specialized compartments that perform their distinct functions through common biophysical properties.

Glycosylation is the most abundant and diverse form of protein post-translational modification. Recent technical developments are enabling the dissection of the glycome in single cells, providing new insights into its regulation and roles in physiology and disease, and new possibilities for controlling glycosylation for therapy.

Non-homologous DNA end joining (NHEJ) is the main repair pathway of DNA double-strand breaks. Recent studies show that synapsis — the crucial pairing of DNA ends — is performed by several mechanisms, and this insight can now be integrated with updates on the DNA end processing and ligation steps of NHEJ, and with NHEJ-related human diseases.

The newest CRISPR–Cas genome editing technologies enable precise and simplified formation of crops with increased yield, quality, disease resistance and herbicide resistance, as well as accelerated domestication. Recent breakthroughs in CRISPR–Cas plant biotechnologies improve reagent delivery, gene regulation, multiplexed gene editing and directed evolution.

Cultured pluripotent stem cells (PSCs) acquire genetic changes — gains or losses of entire chromosomal regions, or point mutations, including in cancer-associated genes such as TP53. Recent work provides insights into the mechanisms of mutation and selection, which have implications for the use of human PSCs in regenerative medicine.

The intestinal epithelium undergoes rapid turnover and is constantly exposed to hostile luminal contents. Recent insights from single-cell transcriptomics and organoid models have revealed that tissue repair is dependent on cell lineage plasticity and signals originating from different niche components.

This Review discusses the cell types, critical genes and transcription factors involved in bone development and repair. The dysfunctional cellular and molecular signalling that results in clinical bone disease is also outlined, thus informing the current state of science and clinical practice.

Dispensable, infected or neoplastic cells are removed by programmed cell death, including pathways for apoptosis, necroptosis and pyroptosis. Owing to differences in their mechanisms and physiological outcomes, these cell death pathways have traditionally been viewed as separate entities, but it has become clear that they are mechanistically and functionally connected.

The nucleolus is a membraneless organelle involved in ribonucleoprotein assembly, including ribosome biogenesis. Recent evidence indicates that the nucleolus is a biomolecular condensate that forms via liquid–liquid phase separation (LLPS), and insights from studies within the LLPS framework are increasing our understanding of the relationship between nucleolar structure and function.

Histone variants differ from canonical histones in their genomic localization, regulation and function. Incorporation of histone variants endows specific genomic regions with unique features to fine-tune gene expression, contributing to animal development and disease pathogenesis.

Human organoids are valuable models for the study of development and disease and for drug discovery, thus complementing traditional animal models. The generation of organoids from patient biopsy samples has enabled researchers to study, for example, infectious diseases, genetic disorders and cancers. This Review discusses the advantages, disadvantages and future challenges of the use of organoids as models for human biology.

Recent studies have highlighted the contribution of RNA to cellular liquid–liquid phase separation and condensate formation. RNA features modulate the composition and biophysical properties of RNA–protein condensates, which have various cellular functions, including RNA transport and localization, supporting catalytic processes and responding to stress.

Different obstacles can stall the progression of replication forks. Recent studies have revealed that stalled forks are remarkably diverse in their composition and architecture. This plasticity enables fork remodelling, processing and restart in response to specific types of replication stress, thereby influencing tumorigenesis and innate immunity.

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 relay cell growth and mitogenic signals to multiple substrates, and thus control essential physiological processes. This Review discusses the regulation of ERKs, and their control of cell proliferation, cell survival, cell growth, cell metabolism, cell migration and cell differentiation.