20th Anniversary

We reflect on the position of Nature Reviews Molecular Cell Biology, 20 years from its launch.

Although the organization of cell membranes into lipid rafts has become a key concept in cell biology, how partitioning of membrane components into subdomains is achieved remains an important question.

Light from a lab’s windows and lamps illuminated the path to the discovery of DNA repair.

Spotlight on Beth Levine’s contributions to autophagy research and its clinical translation.

Roland Wenger highlights discovery of HIFs and recent insights into their differential physiological roles.

A 2017 paper showed that phase separation and formation of elastin in the extracellular matrix does not require protein secondary structures, but cross-linked disordered chains.

Ana García-Sáez highlights the continued interest in BCL-2 proteins and their mechanisms.

Two studies in nematodes revolutionized our understanding of gene regulation by identifying and functionally characterizing the first microRNA, lin-4.

Twenty years ago it was reported that epithelial–mesenchymal transition (EMT), a key developmental process, occurs in cancer; many studies have since, and still are, studying EMT heterogeneity and its functional implications.

Gavin Kelsey discusses the first reports of genomic imprinting in mammals and how they raised the profile of epigenetics in the study of mammalian development.

Sally Lowell discusses the concept of ‘community effect’ when cells commit to a certain differentiation path, which was proposed by John Gurdon in 1988 and recently suggested to enable cancer cells to gain control.

Lipid rafts are relatively ordered membrane domains that are enriched in cholesterol and saturated lipids, and selectively recruit other lipids and proteins. They are dynamic and heterogeneous in composition and are thus challenging to visualizein vivo. New technologies are providing novel insights into the formation, organization and functions of these membrane domains.

The choice between the major DNA double-strand break repair pathways is important for maintaining genomic stability. In mammals, selecting one pathway over another involves a complex series of binary ‘decisions’. Emerging evidence suggests that the ‘decision tree’ governing repair-pathway choice at stalled replication forks differs from that of replication-independent double-strand breaks.

Autophagy is a process of cellular self-consumption that promotes cell survival in response to stress. Various human pathologies, including cancer, neurodegeneration and inflammation, have been associated with aberrant autophagy, and recent studies of the mechanisms and regulation of autophagy in higher eukaryotes have suggested new therapeutic possibilities.

The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms, such as inflammation and wound repair.

In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge.

BCL-2 family proteins have either pro- or anti-apoptotic activities that are crucial for the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. Recent advances suggest that interactions between BCL-2 family proteins affect their localization and conformation and regulate their bioactivity.

BCL-2 family proteins are the mediators of apoptotic cell death. The balance between pro-apoptotic and pro-survival BCL-2 family members is differently regulated in various physiological contexts to modulate cellular apoptotic susceptibility. Perturbation of this balance causes excessive or insufficient cell death, leading to diseases such as neurodegeneration and cancer.

The cleavage of microRNA (miRNA) precursors by Drosha and Dicer and their loading with Argonaute proteins into RNA-induced silencing complexes are key steps in miRNA biogenesis. Recent studies have clarified the mechanisms of action of these molecular machines and discovered non-canonical miRNA biogenesis pathways.

Epithelial–mesenchymal transition (EMT) is an essential process during morphogenesis. Dissecting the signalling strategies that orchestrate EMT have shown that a complex signalling network, which controls adhesion, motility, survival and differentiation, also regulates the initiation and execution of EMT during embryonic development.

Epithelial–mesenchymal transition (EMT) is crucial for embryogenesis, wound healing and cancer development, and confers greater resistance to cancer therapies. This Review discusses the mechanisms of EMT and its roles in normal and neoplastic tissues, the contribution of cell-intrinsic signals and the microenvironment to inducing EMT, and its effects on the immunobiology of carcinomas.

Despite its role in long-term gene silencing, DNA methylation is more dynamic than originally thought. Active DNA demethylation occurs during specific stages of development and there is growing evidence to suggest that multiple mechanisms for active DNA demethylation exist.

DNA methylation in plants mediates gene expression, transposon silencing, chromosome interactions and genome stability. It is therefore not surprising that the regulation of DNA methylation is important for plant development and for plant responses to biotic and abiotic stresses.

This year marks the tenth anniversary of the generation of induced pluripotent stem cells (iPSCs) by transcription factor-mediated somatic cell reprogramming. Takahashi and Yamanaka portray the path towards this ground-breaking discovery and discuss how, since then, research has focused on understanding the mechanisms underlying iPSC generation and on translating such advances to the clinic.

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.