Reviews & Analysis

Nuclear pore complexes (NPCs) are large protein assemblies that form channels in the nuclear envelope and constitute major routes for nucleocytoplasmic communication. Insights into the complex structure of NPCs provide the basis for understanding their functions and reveal how the dysfunction of their structural components, nucleoporins, contributes to human disease.

Several years after the characterization of the role of receptor-interacting serine/threonine protein kinase 1 (RIPK1) in cell survival, inflammation and disease, RIPK1 was implicated in the regulation of a newly identified type of cell death known as necroptosis. This Timeline article describes the discoveries that shed light on the roles of RIPK1, RIPK3, mixed-lineage kinase domain-like protein (MLKL) and other regulators of necroptosis in controlling cell fate.

In addition to acetylation, eight types of structurally and functionally different short-chain acylations have recently been identified as important histone Lys modifications: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These modifications are regulated by enzymatic and metabolic mechanisms and have physiological functions, which include signal-dependent gene activation and metabolic stress.

Histone variants are typically incorporated into chromatin independently of DNA replication and modify chromatin properties. Recent studies have elucidated how particular histone variants are substrates of histone chaperones, chromatin remodellers and histone-modifying enzymes, thereby modifying DNA replication and repair, transcription and chromatin packaging.

Human pluripotent stem cells constitute a unique system to study the earliest stages of human embryonic haematopoiesis and the origins of human blood cell diseases, and they are an invaluable tool for the generation of haematopoietic stem and progenitor cell populations for cell-based regenerative therapies.

Genetic variants can produce phenotypic traits through effects on RNA processing, including effects on pre-mRNA splicing, 3′ end formation, and RNA stability, localization, structure and translation efficiency.

Mutations in non-coding parts of the genome can cause disease. Technological advances are providing unprecedented detail on genome organization and folding, and have revealed that enhancer–target gene coupling is spatially restricted, as it occurs within topologically associated domains (TADs), and that disrupting such organization can lead to disease-associated gene dysregulation.

Reversible mRNA methylation is an emerging mode of eukaryotic post-transcriptional gene regulation.N⁶-methyladenosine (m⁶A) affects mRNA processing, translation and decay during cell differentiation, embryonic development and stress responses. Other mRNA modifications — N¹-methyladenosine (m¹A), 5-methylcytosine (m⁵C) and pseudouridine — together with m⁶A code a new layer of information that controls protein synthesis.

Mechanistic insights are emerging into how long non-coding RNAs (lncRNAs) regulate gene expression by coordinating regulatory proteins, localizing to genomic loci and shaping nuclear organization. Interestingly, lncRNAs can perform functions that cannot be carried out by DNA elements or proteins alone, such as amplifying regulatory signals in the nucleus.

Steroid hormone receptors are well known to regulate various aspects of animal physiology by acting as transcriptional regulators in the nucleus. However, it is now evident that these receptors can also be targeted to extranuclear locations (such as the plasma membrane), where they instigate rapid signals that contribute to steroid-mediated cellular responses.

New observations of ESCRT-mediated reverse-topology membrane scission are building towards a structural and biophysical explanation of the mechanism involved.

Alternative polyadenylation (APA) generates mRNAs with varying 3′ termini. It is regulated by variation in the concentration of cleavage and polyadenylation factors and by RNA-binding proteins, as well as by splicing and transcription. APA is important for cell proliferation and differentiation owing to its roles in mRNA metabolism and protein diversification.

Contact inhibition of locomotion (CIL) involves collisions with other cells during cell migration that typically induce cessation of movement or a change of migratory direction. A molecular description of CIL and details of its involvement in various cellular processes are emerging, demonstrating that CIL is a highly heterogeneous response with important functionsin vivo.

Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, thereby mediating chromatin dynamics and stability, transcription, replication and DNA damage repair. Topoisomerases are targets of various anticancer drugs, and their deregulation can cause, in addition to cancer, neurodegenerative diseases and immune disorders.

The establishment of various coexisting actin networks supports a plethora of cellular processes and functions. How actin incorporation into these different networks is regulated to balance their growth and maintain homeostasis has remained elusive. Here, the authors propose that the internetwork competition for a limited pool of actin monomers underlies the homeostatic control of actin cytoskeleton organization.

The three-dimensional (3D) organization of eukaryote chromosomes regulates genome function and nuclear processes such as DNA replication, transcription and DNA-damage repair. Experimental and computational methodologies for 3D genome analysis have been rapidly expanding, with a focus on high-throughput chromatin conformation capture techniques and on data analysis.

Brown adipocytes (which reside in brown adipose tissue) and beige adipocytes (which develop in white adipose tissue in response to cold) expend energy to produce heat and are therefore important in regulating body temperature and body weight. Recent studies provide insights into the developmental origins of brown and beige adipocytes and into the regulation of their differentiation and function.

Sirtuins are NAD⁺-dependent protein deacylases that can reverse various aspects of ageing in model organisms. Trials in non-human primates and humans indicate that sirtuin-activating compounds (STACs) and NAD⁺precursors are safe and effective in treating inflammatory and metabolic disorders, thereby holding great potential to treat various diseases and to extend lifespan in humans.

The DNA of mammalian cells can be damaged by various endogenous and exogenous insults, leading, if unrepaired, to genomic instability. Recently it has become apparent that bacterial pathogens can be a source of genomic instability, owing to their combined capacity to incur DNA damage and to interfere with DNA repair pathways.

The Notch signalling pathway functions in many processes — from developmental patterning to cell growth and cell death. As the complexity of Notch signalling regulation is being unravelled at the levels of cell-surface ligand–receptor interactions and of gene expression, we are gaining a deeper understanding of how this conserved pathway can lead to such diverse cellular responses.