Reviews & Analysis

The conservation and prevalence of inactive homologues in most enzyme families suggests that they may have significant functions that have been largely overlooked. Mechanistic understanding and evolutionary lessons are now emerging from the study of a broad range of such 'dead' enzymes including the recently discovered iRhoms.

The identification of an hydrogen sulfide (H₂S)-mediated post-translational modification (protein sulfhydration) has provided novel insights into H₂S signalling, which controls many cellular functions. As a result, a new research area has arisen that investigates how metabolic stress and other environmental signals influence protein function through Cys modification by H₂S.

Chromatin compaction has profound implications for the regulation of transcription, replication and DNA repair. Changes in nucleosome structure and stability — due to the incorporation of variant histones and post-translational modifications of histones — affect chromatin compaction. Chromatin structures are not nearly as uniform as previously assumed, which should be taken into account in the context of specific biological functions.

Approximately half of human proteins are glycosylated, and the resulting diverse glycan patterns encode an additional level of information. The process of protein glycosylation is mediated by numerous enzymes with dynamic localization, regulation and specificity. High-throughput techniques facilitate the study of complex protein glycans and may give further insights into their roles in protein homeostasis, cell signalling and cell adhesion.

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein modification, the control of which is important for diverse cell biological processes and normal physiology. Common mechanistic themes are being characterized by which PARylation alters the functions of target proteins, and the PAR-binding modules that mediate this.

The centriole is crucial for the formation of flagella, cilia and centrosomes. The ultrastructure of the centriole reveals a striking ninefold radial arrangement of microtubules. Emerging insights into the molecular mechanisms of centriole assembly include the function of spindle assembly abnormal 6 (SAS-6) proteins in imparting the ninefold symmetry.

The glucose transporter GLUT4 ensures controlled glucose uptake into fat and muscle cells. By targeting several steps in the membrane trafficking of GLUT4, insulin signalling allows tight regulation of glucose homeostasis and prevents the development of insulin resistance.

Traditionally, ribosomes have been viewed as invariable complexes with ubiquitous function in mRNA translation. However, ribosome specialization, resulting from the differential expression and cell type-specific modification of its components, seems to greatly contribute to the diversity of biological processes.

During the first division of meiosis, homologous chromosomes are pulled to opposite poles and segregated to daughter cells. This form of chromosome segregation, which differs from what occurs in mitosis, is facilitated by meiosis-specific changes to chromosomes as well as by kinetochore geometry and tension exerted by microtubules.

The TFIIH complex has an integral role in both nucleotide excision repair and transcription. Studies of TFIIH are therefore defining a new model for crosstalk between the factors that orchestrate DNA repair and transcription, as well as the concept of 'transcription diseases'.

O-GlcNAcylation is a post-translational modification that seems to regulate the function of numerous target proteins in a nutrient-sensitive manner. Recent evidence suggests an important role forO-GlcNAcylation in epigenetic regulation.

Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Unravelling its enzymatic activities, its signalling partners, and the molecular mechanisms involved in the multiple levels of PTEN regulation will aid the design of novel PTEN-based therapeutic interventions in cancer.

Histone demethylases are important for both chromatin structure and transcription. The insights being gained into their regulation and target specificity have important implications for both normal development and disease.

AMPK acts as an intracellular energy sensor, as its activity is tuned by the relative levels of ATP, ADP and AMP. Therefore, it has a central role in the regulation of cellular metabolic pathways and in the control of whole-body energy balance.

MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b control cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. miRNAs also regulate insulin and glucose homeostasis. Thus, miRNAs may be potential therapeutic targets for ameliorating cardiometabolic disorders.

Nuclear receptors integrate hormonal and nutritional signals, resulting in changes to key metabolic pathways within the body. The liver X receptor (LXR) and the farnesoid X receptor (FXR), which are activated by oxysterols and bile acids, respectively, have essential roles in the regulation of cholesterol and bile acid metabolism but are also key integrators of sterol, fatty acid and glucose metabolism.

Sirtuins are a family of deacetylases that target histones and proteins in several cellular compartments. Sirtuins are crucial regulators of energy homeostasis, as they detect physiological changes in energy levels and modulate glucose and lipid metabolism accordingly. As such, they affect health in a pleiotropic manner.

The influence of chromatin structure on the DNA replication programme is reciprocated by replication-coupled mechanisms that re-establish chromatin on newly formed DNA. The tight coupling of these processes is essential for promoting integrity of the genome and epigenome, with possible implications for ageing and cancer.

The Y-family DNA polymerases have unique features that enable them to synthesize DNA past damaged bases, a process known as translesion synthesis. As these polymerases copy undamaged DNA with low fidelity, their activity must be tightly regulated.

The incorporation of unnatural amino acids at defined sites in proteins can now be used to probe protein conformational changes, protein interactions and the role of post-translational modifications in regulating biological function. The use of photocaged amino acids and bio-orthogonal labels for proteins holds great promise for cell biological studies in live cells.