Reviews & Analysis

Lipolysis degrades triacylglycerols to supply cells with free fatty acids, which are essential components of membrane lipids and substrates for energy production. Recent discoveries transformed our understanding of the functions of and crosstalk between 'neutral' lipolysis, which occurs in the cytosol, and lipophagy and 'acid' lipolysis, which occur in lysosomes, and how dysfunction in these processes contributes to metabolic diseases.

Heat shock transcription factors (HSFs) regulate heat shock proteins in conditions of thermal stress, but they also control gene expression in other stress conditions, as well as in other contexts, including the regulation of cell proliferation and energy metabolism. HSFs are misregulated in various diseases, such as cancer and neurodegeneration, which underlines their important physiological roles.

Assembly of the microtubule nucleus is energetically unfavourable and,in vivo, microtubule nucleation requires support, such as a stable template, to stabilize the initial weak interactions between tubulin dimers. Microtubules can also be nucleated in the absence of a template by certain microtubule-associated proteins, which stabilize the nascent nucleation intermediates.

Replication stress is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR), which senses and resolves threats to DNA integrity. ATR activation is complex and involves a core set of components that recruit ATR to stressed replication forks, stimulate its kinase activity and amplify downstream signalling to maintain the stability of replication forks.

Mitochondrial disorders encompass a broad range of pathologies, which manifest in different tissues, with variable age of onset and symptoms. Recent findings suggest that mitochondrial stress responses, which are activated by defects in mitochondrial genome maintenance and expression, contribute to cell and systemic dysfunction, and could explain the phenotypic variability of mitochondrial disorders.

The majority of common diseases are associated with ageing. Diseases that cause premature ageing serve as natural model systems for studying the mechanisms of ageing and disease, as they share similar cellular and molecular hallmarks, including genomic instability, metabolic defects and loss of regenerative capacity.

Pre-mRNA splicing occurs on nascent RNA, which is attached to chromatin by RNA polymerase II. Much splicing occurs co-transcriptionally, and the spatial and temporal coordination of the two processes is tightly coordinated with other mRNA-processing events.

Motile and non-motile primary cilia are nearly ubiquitous cellular organelles. Dysfunction of cilia is being found to cause increasing numbers of diseases that are known as ciliopathies. The characterization of ciliopathy-associated proteins and phenotypes is increasing our understanding of how cilia are formed and compartmentalized and how they function to maintain human health.

Recent insights into the roles of poly(ADP-ribose) polymerase 1 (PARP1) in mediating various DNA repair pathways, stabilizing DNA replication and modulating chromatin structure are being exploited clinically for the treatment of DNA repair-deficient cancers.

Covalent DNA–protein crosslinks (DPCs) are induced by various compounds, which include widely used anticancer drugs, and are highly cytotoxic. Recent studies have revealed the mechanisms and the regulation of DPC repair pathways and suggest that components of these pathways can serve as targets for anticancer therapies.

The presence of nucleosomes and their substructures affects local chromatin structure and function. Thus, nucleosome occupancy, their exact positioning and composition need to be dynamically regulated. Advances in genomic technologies have improved our understanding of nucleosome dynamics in various cellular processes, most notably DNA replication and transcription.

Blood and lymphatic vessels have essential roles in physiology and disease. The endothelial cells that line these vessels specialize to fulfil the needs of the tissue that they pervade. Recent studies in animal models have provided insights into the mechanisms underlying vessel type- and organ-specific specialization, which is crucial for the understanding of several diseases.

The termination of DNA replication involves convergence of replication forks, the completion of DNA synthesis, replisome disassembly and the decatenation of daughter DNA molecules. Recent discoveries illustrate how replisome disassembly in eukaryotes is controlled by E3 ubiquitin ligases and how this activity is regulated to avoid genome instability.

Nucleosome-remodelling complexes can slide or eject histones, or incorporate histone variants, but they share an ATPase–translocase 'motor' and a common DNA translocation mechanism. In a unifying 'hourglass' model of remodeller function, the different remodeller subfamilies use different modules for targeting to nucleosomes but converge on a DNA translocation mechanism and then diverge again to achieve various outcomes.

In mammalian cells, DNA double-strand breaks (DSBs) are repaired predominantly by the non-homologous end joining (NHEJ) pathway, which includes subpathways that can repair different DNA-end configurations. Furthermore, the repair of some DNA-end configurations can be shunted to the auxiliary pathways of alternative end joining (a-EJ) or single-strand annealing (SSA).

Alternative splicing expands the complexity of the proteome by generating multiple transcript isoforms from a single gene. Numerous alternative splicing events occur during cell differentiation and tissue maturation, suggesting that alternative splicing supports proper development. Recent studies shed light on how alternative splicing and its coordination contribute to organ development and tissue homeostasis.

Many cellular proteins are reversibly modified byO-linked N-acetylglucosamine (O-GlcNAc) moieties on Ser and Thr residues. Studies on the mechanisms and functions of O-GlcNAcylation and its links to metabolism reveal the importance of this modification in the maintenance of cellular and organismal homeostasis.

The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases.

Multiciliated cells line the lumen of the vertebrate central nervous system and respiratory and reproductive tracts, where the unidirectional beating of cilia assemblies supports the polarized flow of fluids or movement of cells or particles. Recent studies shed new light on how multiciliated cells arise and how they function.

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.