Reviews & Analysis

Cholesterol is an important structural component of all animal cell membranes that functions in various processes, including membrane dynamics and cell signalling, and is also a precursor of other molecules. Deregulation of cholesterol metabolism — biosynthesis, dietary absorption and cellular uptake, storage and efflux — is linked to many diseases, including cardiovascular and genetic diseases, and cancer. A better understanding of cholesterol metabolism offers the possibility to control systemic cholesterol levels to improve human health.

Animal circadian rhythms are controlled by central and peripheral molecular clocks, whose components generate oscillations in their own abundance and activity. Insights into how these clocks time the function of organs and tissues is increasing our understanding of animal physiology.

Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.

AAA+ proteins are macromolecular machines that remodel a vast array of cellular substrates, including protein aggregates, macromolecular complexes and polymers. Recent advances in cryo-electron microscopy have enabled visualization of them while in action, leading to a better understanding of the mechanisms of engagement and processing of their diverse substrates.

Although organelles compartmentalize eukaryotic cells, they can communicate and integrate their activities by connecting at membrane contact sites (MCSs). The roles of MCSs in biology are becoming increasingly clear, with MCSs now known to function in intracellular signalling, lipid metabolism, membrane dynamics, organelle biogenesis and the cellular stress response.

Endosomal sorting complexes required for transport (ESCRTs) are key membrane remodellers, which drive the budding, scission and sealing of various cellular membranes. Accordingly, ongoing research focuses on how ESCRTs mediate a wide-range of cellular processes, including cytokinesis, endosome maturation, autophagy, membrane repair and viral replication.

Novel methods for tracking the progeny of single cells involve prospective lineage tracing, in which DNA barcodes are introduced into single cells and tracked over time, or retrospective lineage tracing, in which somatic mutations are used as DNA barcodes. These methods improve our understanding of cell fates in development, cell differentiation and tissue regeneration.

Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

When cells migrate through complex 3D environments, as are most tissues, they encounter several challenges, including the need to adapt to changing biomechanical properties of the surroundings, squeezing through narrow passages and coordinating motion with other cells. A better understanding of 3D cell migration mechanisms provides key insights into development, tissue regeneration, immune responses and cancer cell dissemination.

Transcription-blocking DNA lesions (TBLs) cause transcription stress and are repaired by transcription-coupled nucleotide excision repair (TC-NER). TBL detection by the stalling of RNA polymerase II is highly efficient but may interfere with repair, and overall with transcription and replication. Consequently, TC-NER deregulation causes hereditary disorders with complex genotype–phenotype correlations.

N ⁶-methyladenosine (m⁶A) is the most abundant mRNA internal modification. The recent mapping of m⁶A has provided insights into which and how mRNAs are modified, how m⁶A affects gene expression and how it is linked to cellular differentiation, cancer progression and other biological processes.

Different genomic regions are replicated at different times during the S phase of the cell cycle, forming early- and late-replicating domains that occupy different locations in the nucleus. The recent identification of specific DNA sequences and long non-coding RNAs that regulate DNA replication timing is providing key insights into the roles of replication timing and into timing and 3D organization.

Predicting how proteins fold enables inferring their function. Conversely, rational protein design allows for engineering novel protein functionalities. Recent improvements in computational algorithms and technological advances have dramatically increased the accuracy and speed of protein structure modelling, providing novel opportunities for controlling protein function, with potential applications in biomedicine, industry and research.

DNA methylation is essential for mammalian embryogenesis owing to its repression of transposons and genes, but it is also associated with gene activation. The recent use of sensitive technologies has revealed that DNA methylation dynamics vary considerably between embryonic, germline and somatic cell development, with implications for genetic diseases and cancer.

The methylation of arginine residues regulates gene expression, DNA repair, growth factor signalling and liquid–liquid phase separation. Targeting this modification can thus be therapeutically relevant and inhibitors of arginine methylation are being tested in clinical trials, especially for neurodegenerative diseases and cancer.

The dynamic methylation of chromatin components — DNA, histones and RNA — is crucial in development, ageing and cancer. Therapies that target regulators of DNA and histone methylation in cancer have recently been developed. These promising therapies, which include strategies that may improve tumour immune surveillance, are already being tested in early-phase clinical trials.

Histone methylation regulates gene expression throughout animal development, governing processes as diverse as cell fate decisions, lineage specification, body patterning and organogenesis. Better understanding of the complex, context-specific roles of histone methylation in development will shed new light on the aetiology of developmental disorders.

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.

The Hsp70 chaperones regulate protein metabolism, including folding, unfolding, subcellular localization, aggregation/disaggregation and incorporation into protein complexes. Recent studies have revealed the mechanisms of functions of Hsp70s and their co-chaperones, highlighting new opportunities for modulating disease-related Hsp70 roles.

The respiratory system comprises multiple cell types, and consequently its development and regeneration involves intricate cellular crosstalk. Better understanding of these complex cellular interactions will improve the treatment of respiratory diseases and tissue repair after injury.