Nature Reviews. Molecular Cell Biology

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No abstract text is available yet for this article.

Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation...

The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool...

In sexually reproducing organisms, life begins with the fusion of transcriptionally silent gametes, the oocyte and sperm. Although initiation of transcription in the embryo, known as zygotic genome activation (ZGA), is universally required for development, the transcription factors regulating this process are poorly conserved. In this Perspective, we discuss recent insights into the mechanisms of ZGA in totipotent mammalian embryos, namely ZGA regulation by several transcription factors, including by orphan nuclear receptors (OrphNRs) such as the pioneer transcription factor NR5A2, and by factors of the DUX, TPRX and OBOX families...

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Integrin receptors are the main molecular link between cells and the extracellular matrix (ECM) as well as mediating cell-cell interactions. Integrin-ECM binding triggers the formation of heterogeneous multi-protein assemblies termed integrin adhesion complexes (IACs) that enable integrins to transform extracellular cues into intracellular signals that affect many cellular processes, especially cell motility. Cell migration is essential for diverse physiological and pathological processes and is dysregulated in cancer to favour cell invasion and metastasis...

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No abstract text is available yet for this article.

No abstract text is available yet for this article.

Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders...

Mechanical force is an essential physical element that contributes to the formation and function of life. The discovery of the evolutionarily conserved PIEZO family, including PIEZO1 and PIEZO2 in mammals, as bona fide mechanically activated cation channels has transformed our understanding of how mechanical forces are sensed and transduced into biological activities. In this Review, I discuss recent structure-function studies that have illustrated how PIEZO1 and PIEZO2 adopt their unique structural design and curvature-based gating dynamics, enabling their function as dedicated mechanotransduction channels with high mechanosensitivity and selective cation conductivity...

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The extracellular matrix (ECM) is the complex meshwork of proteins and glycans that forms the scaffold that surrounds and supports cells. It exerts key roles in all aspects of metazoan physiology, from conferring physical and mechanical properties on tissues and organs to modulating cellular processes such as proliferation, differentiation and migration. Understanding the mechanisms that orchestrate the assembly of the ECM scaffold is thus crucial to understand ECM functions in health and disease. This Review discusses novel insights into the compositional diversity of matrisome components and the mechanisms that lead to tissue-specific assemblies and architectures tailored to support specific functions...

DNA methylation, also known as 5-methylcytosine, is an epigenetic modification that has crucial functions in plant growth, development and adaptation. The cellular DNA methylation level is tightly regulated by the combined action of DNA methyltransferases and demethylases. Protein complexes involved in the targeting and interpretation of DNA methylation have been identified, revealing intriguing roles of methyl-DNA binding proteins and molecular chaperones. Structural studies and in vitro reconstituted enzymatic systems have provided mechanistic insights into RNA-directed DNA methylation, the main pathway catalysing de novo methylation in plants...

Single-cell transcriptomics has broadened our understanding of cellular diversity and gene expression dynamics in healthy and diseased tissues. Recently, spatial transcriptomics has emerged as a tool to contextualize single cells in multicellular neighbourhoods and to identify spatially recurrent phenotypes, or ecotypes. These technologies have generated vast datasets with targeted-transcriptome and whole-transcriptome profiles of hundreds to millions of cells. Such data have provided new insights into developmental hierarchies, cellular plasticity and diverse tissue microenvironments, and spurred a burst of innovation in computational methods for single-cell analysis...

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Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy-lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia...

Voltage-gated ion channels (VGICs), including those for Na+ , Ca2+ and K+ , selectively permeate ions across the cell membrane in response to changes in membrane potential, thus participating in physiological processes involving electrical signalling, such as neurotransmission, muscle contraction and hormone secretion. Aberrant function or dysregulation of VGICs is associated with a diversity of neurological, psychiatric, cardiovascular and muscular disorders, and approximately 10% of FDA-approved drugs directly target VGICs...