Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway — alternative end joining (a-EJ) — has long resisted elucidation. In this Review, we highlight recent progress in our understanding of a-EJ, especially the assignment of DNA polymerase

Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic

The expanding scale and inherent complexity of biological data have encouraged a growing use of machine learning in biology to build informative and predictive models of the underlying biological processes. All machine learning techniques fit models to data; however, the specific methods are quite varied and can at first glance seem bewildering. In this Review, we aim to provide readers with a gentle

Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints

Xu et al. report engineering a compact version of Cas that can be useful for a broad range of genome engineering applications in mammalian cells.

Tau oligomers bind to m6A-modified RNA transcripts in the cytoplasm via the linker RNA-binding protein HNRNPA2B1; such complexes are found in individuals with Alzheimer disease and are part of a stress response that represses translation.

The protein kinase ataxia telangiectasia mutated (ATM) is a master regulator of double-strand DNA break (DSB) signalling and stress responses. For three decades, ATM has been investigated extensively to elucidate its roles in the DNA damage response (DDR) and in the pathogenesis of ataxia telangiectasia (A-T), a human neurodegenerative disease caused by loss of ATM. Although hundreds of proteins have

Base excision repair promotes transcriptional noise, which likely increases cell responsiveness to cell-type-specification cues.

Microtubule dynamics and their control are essential for the normal function and division of all eukaryotic cells. This plethora of functions is, in large part, supported by dynamic microtubule tips, which can bind to various intracellular targets, generate mechanical forces and couple with actin microfilaments. Here, we review progress in the understanding of microtubule assembly and dynamics, focusing

Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear that chromatin and histone post-translational modification have fundamental roles in gene regulation. Polycomb repressive complexes represent a paradigm

In the race to publish papers and secure funding, science can sometimes seem like a competition. But, in reality, modern science relies on open sharing and collaboration. One unexpected aspect of open science is the role it has played in uplifting the careers of myself and my lab members. Drawing from his personal experience, Neville Sanjana highlights how open science benefits academic careers.

Garabedian et al. developed designer biomolecular condensates serving as tools for flexible interrogation and temporal regulation of cell functions.

Biomolecular condensates, regardless of whether they exhibit liquid-like properties, are in many cases not fully amorphous, but instead exhibit partial degrees of local structure and order. Here, we discuss how ordered interactions may underlie the cooperative assembly and cellular function of a wide variety of partially ordered macromolecular assemblies. In this Comment, the authors draw attention

Suppressing ovulation protects against chromosomal abnormalities in ageing mouse oocytes, which can be partly explained by increasing REC8–cohesin retention on chromosomes.

Gene regulation requires the dynamic coordination of hundreds of regulatory factors at precise genomic and RNA targets. Although many regulatory factors have specific affinity for their nucleic acid targets, molecular diffusion and affinity models alone cannot explain many of the quantitative features of gene regulation in the nucleus. One emerging explanation for these quantitative properties is that

Building a research programme in a competitive field is a daunting journey that most, if not all, new faculty navigate as they begin their independent career. This journey can be an enjoyable adventure as we carve out our own unique space in the vast landscape of biological science. Jonathon Ditlev shares his thoughts on building a research programme in a competitive field.

RNA interference mediated by a Dicer isoform protects mammalian stem cells against RNA viruses.

Meng Wang discusses the importance of early studies that led to the discovery of genes that regulate longevity.

Autophagy is a versatile degradation system for maintaining cellular homeostasis whereby cytosolic materials are sequestered in a double-membrane autophagosome and subsequently delivered to lysosomes, where they are broken down. In multicellular organisms, newly formed autophagosomes undergo a process called ‘maturation’, in which they fuse with vesicles originating from endolysosomal compartments

Izabela Sumara highlights the work by Beck and colleagues that identified a pathway for the biogenesis of nuclear pore complexes, which involves annulate lamellae and biomolecular condensates containing nucleoporins.

Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues — prominently in muscle, fat and liver — is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia

Recent studies invoke phase separation as a mechanism underlying the formation of ‘transcriptional condensates’. However, similarities between transcriptional condensates and the previously introduced ‘transcription factories’ model raise the question of what distinguishes the two models. One crucial aspect to consider is the contribution of intrinsically disordered regions in transcription-relevant

Stem cells are characterized by their ability to self-renew and differentiate into many different cell types. Research has focused primarily on how these processes are regulated at a transcriptional level. However, recent studies have indicated that stem cell behaviour is strongly coupled to the regulation of protein synthesis by the ribosome. In this Review, we discuss how different translation mechanisms

The pathogenicity of SARS-CoV-2 and respiratory syncytial virus (RSV) involves mechanisms of liquid–liquid phase separation, which can be explored as targets for new antiviral therapeutics.

Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue — encompassing the muscle cells (myofibres) themselves and their extracellular matrix — or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder — mutations in dystrophin as an

Apoptotic hair follicle stem cells contribute to tissue regeneration by producing WNT3, which promotes cell proliferation, enlarging the stem cell pool.

A familial connection to disease can motivate a career in the biological sciences. However, tension may exist over how much effort to devote to fundamental versus translational research. In reality, both pursuits are symbiotic — they synergize to advance our understanding of life and the development of effective therapeutics. Eric Wang’s familial connection to disease raised tension between efforts

In response to replication stress, TOPBP1 is recruited by Treacle to nucleoli, where the two proteins facilitate the stress response and help maintain the transcription of rRNA genes.

In multicellular systems, oriented cell divisions are essential for morphogenesis and homeostasis as they determine the position of daughter cells within the tissue and also, in many cases, their fate. Early studies in invertebrates led to the identification of conserved core mechanisms of mitotic spindle positioning centred on the Gαi–LGN–NuMA–dynein complex. In recent years, much has been learnt

The human genome contains more than one million short tandem repeats, and expansion of a subset of these repeat tracts underlies more than 50 human disorders. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding

Torrino et al. show that the stiffness of the extracellular matrix regulates microtubule posttranslational modification via glutamylation, which impacts microtubule dynamics and cell invasiveness.

Migrasomes function as a mitochondrial quality control mechanism in migrating cells, and affect neutrophil viability.

CRISPR loci and Cas proteins provide adaptive immunity in prokaryotes against invading bacteriophages and plasmids. In response, bacteriophages have evolved a broad spectrum of anti-CRISPR proteins (anti-CRISPRs) to counteract and overcome this immunity pathway. Numerous anti-CRISPRs have been identified to date, which suppress single-subunit Cas effectors (in CRISPR class 2, type II, V and VI systems)

Nuclear condensates of m6A-methylated mRNAs with their ‘reader’ YTHDC1 prevent the degradation of acute myeloid leukaemia-promoting mRNAs by the exosome.

Liver regeneration is a complex process involving the crosstalk of multiple cell types, including hepatocytes, hepatic stellate cells, endothelial cells and inflammatory cells. The healthy liver is mitotically quiescent, but following toxic damage or resection the cells can rapidly enter the cell cycle to restore liver mass and function. During this process of regeneration, epithelial and non-parenchymal

Endocytosis allows cells to transport particles and molecules across the plasma membrane. In addition, it is involved in the termination of signalling through receptor downmodulation and degradation. This traditional outlook has been substantially modified in recent years by discoveries that endocytosis and subsequent trafficking routes have a profound impact on the positive regulation and propagation

Dwivedi et al. now show that DNA replication stress is an important trigger for cell extrusion.

Cells have the ability to respond to various types of environmental cues, and in many cases these cues induce directed cell migration towards or away from these signals. How cells sense these cues and how they transmit that information to the cytoskeletal machinery governing cell translocation is one of the oldest and most challenging problems in biology. Chemotaxis, or migration towards diffusible

Elif Nur Firat-Karalar brings to our attention the early works by Sergei Sorokin that paved the way for research into the biogenesis and function of primary cilia.

The histone reader PHF7 binds to cardiac super-enhancers and is a strong activator of the reprogramming of adult cardiac fibroblasts to induced cardiac-like myocytes.

The transcription factor p53 boosts the expression of a distinct subset of its target genes by enhancing their association with nuclear speckles.

Understanding how chromatin is folded in the nucleus is fundamental to understanding its function. Although 3D genome organization has been historically difficult to study owing to a lack of relevant methodologies, major technological breakthroughs in genome-wide mapping of chromatin contacts and advances in imaging technologies in the twenty-first century considerably improved our understanding of

Jenna Jewell discusses two papers that spearheaded the work towards understanding amino acid sensing by mTORC1.

Krista Varady discusses two seminal papers on intermittent fasting that inspired her to enter this research area.

The cytoskeleton — comprising actin filaments, microtubules and intermediate filaments — serves instructive roles in regulating cell function and behaviour during development. However, a key challenge in cell and developmental biology is to dissect how these different structures function and interact in vivo to build complex tissues, with the ultimate aim to understand these processes in a mammalian

Roney et al. show that neuronal loss in Niemann-Pick disease type C is associated with the impairment of lysosome trafficking by cholesterol that accumulates on lysosome membranes.

Samira Musah highlights work by Puelles et al. investigating multi-organ affinity of SARS-CoV-2 and its high infectivity of the kidneys.

Roukos and Longo recount the findings of two 1982 papers, which proved that chromosomes and spaghetti are not alike.

Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution imaging technologies to detect mRNAs and their translation state have revealed that all living organisms localize mRNAs in subcellular compartments and create translation hotspots, enabling cells to tune gene expression locally. Therefore

Stromal progenitors are found in many different tissues, where they play an important role in the maintenance of tissue homeostasis owing to their ability to differentiate into parenchymal cells. These progenitor cells are differentially pre-programmed by their tissue microenvironment but, when cultured and stimulated in vitro, these cells — commonly referred to as mesenchymal stromal cells (MSCs)

Sunil Laxman highlights the 1987 discovery of cyclic-di-GMP, which prompted scientists to rethink the concept of ‘unicellular’ and the impact of cell signalling.

We propose a mechanism underlying polyglutamine (polyQ) repeat expansion diseases, in which the translation of expanded CAG codon repeats leads to translation stress. The stress is generated by depletion of the cognate glutaminyl-tRNA pool, which could cause ribosome frameshifting and lead to mistranslation of transcripts with specific characteristics. Michele Vendruscolo and colleagues propose that

Nicolas Papon highlights the work by Kakimoto and colleagues that led to the identification of the cytokinin receptor in plants — 20 years ago.

Unexpected high levels of recurrent DNA single-strand break repair were detected in enhancer regions of post-mitotic neurons.

Lancaster and colleagues describe a morphological change in early primate brain stem cells, the timing of which could underlie the differences in brain size between human and apes.

In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including

Genomic DNA is folded into loops and topologically associating domains (TADs), which serve important structural and regulatory roles. It has been proposed that these genomic structures are formed by a loop extrusion process, which is mediated by structural maintenance of chromosomes (SMC) protein complexes. Recent single-molecule studies have shown that the SMC complexes condensin and cohesin are indeed