Reviews & Analysis

In mammalian cells, several proteins that are not part of the core replication machinery promote the efficient restart of stalled replication forks, which suggests that fork restart pathways exist. Different models of restart can be envisaged, which involve DNA helicases, nucleases, homologous recombination factors and DNA double-strand breaks.

Although necrosis was regarded as an uncontrolled mode of cell death, evidence now shows that it can be highly regulated. The initiation of programmed necrosis (necroptosis) by death receptors requires receptor-interacting protein 1 (RIP1) and RIP3, and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes.

Non-vesicular lipid transport between intracellular membranes can be mediated by spontaneous lipid transfer or lipid-transfer proteins (LTPs) and is crucial for maintaining the identities of different cellular membranes. Current studies focus on further understanding the mechanisms of non-vesicular lipid transport and elucidating the role of LTPs in intact cells.

Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. Adhesion formation and disassembly drive the migration cycle by activating Rho GTPases, which in turn regulate actin polymerization and myosin II activity, and therefore adhesion dynamics.

Proteomic studies have led to the identification of numerous new transport components and pathways for mitochondrial protein import. Furthermore, they have revealed that protein translocases are integrated into dynamic networks and are connected to machineries that function in bioenergetics, mitochondrial morphology and coupling to the endoplasmic reticulum.

Preserving a functional set of cytoplasmic organelles requires accurate organelle inheritance at cell division. In yeast, the polarized transport of peroxisomes to daughter cells is balanced by retention mechanisms. Some mechanistic principles apply to the inheritance of all organelles, but the inheritance of some organelles is regulated by specific factors.

Aminoacyl tRNA synthetases (aaRSs) have progressively added domains and motifs that have no connection to aminoacylation. These additions equip aaRSs with new functions and correlate with the appearance of new biological processes (such as a circulatory system) during the course of evolution.

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.

Mitochondrial outer membrane permeabilization is often required for activation of the caspase proteases that cause apoptotic cell death. As a consequence, the integrity of the mitochondrial outer membrane is highly controlled, primarily through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family.

Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This functional diversity is driven by their interaction with J proteins — a diverse class of cofactors.

Despite decades of research, the extent to which human progerias resemble accelerated ageing is still unclear and highly debated. Understanding this connection will require the ongoing characterization of genetic pathways that influence the ageing process in model systems and investigations into molecular pathways that define the pathogenesis of human progerias.

Heat shock factors (HSFs) are essential for survival in a stressful environment. HSFs mediate the heat shock response by binding heat shock elements present in heat shock protein (HSP) genes, thereby mediating their transcription. They are also important regulators of development, lifespan and disease.

Recent work has advanced our understanding of the molecular organization of adherens junctions and how cadherin–catenin complexes at their core engage actin, microtubules and the endocytic machinery. This provides insight into how adherens junctions can maintain tissue architecture and facilitate cell movement during tissue morphogenesis.

The nuclear pore complex is the key regulator of transport between the cytoplasm and nucleus. Emerging evidence suggests it also regulates gene expression by influencing the internal architecture of the nucleus and by coordinating the delivery of genetic information to the cytoplasmic protein synthesis machinery.

The endosomal sorting complex required for transport (ESCRT) machinery catalyses membrane budding in the endolysosomal pathway, which differs from other budding events in that it is directed away from the cytosol. Recent studies have elucidated a mechanism whereby ESCRT-I and ESCRT-II stabilize the bud neck and ESCRT-III mediates neck cleavage.

Monoubiquitylation and polyubiquitylation by Lys63-linked chains contribute to three different pathways related to the maintenance of genome integrity that are responsible for the processing of DNA double-strand breaks, the repair of interstrand cross links and the bypass of lesions during DNA replication.

HSP90 is a highly conserved chaperone that facilitates the maturation of a wide range of proteins. Recent studies have provided insight into the regulation of the HSP90 chaperone cycle and revealed numerous processes that HSP90 regulates directly or indirectly.

Recent studies suggest that the spindle matrix provides a conserved strategy to coordinate the segregation of genetic material and the partitioning of other cellular contents in open, partially open and closed mitosis.

Recent discoveries have identified several striking parallels between the cellular factors and molecular events that govern mRNA degradation in eukaryotes and bacteria. Nevertheless, some key distinctions remain, the most fundamental of which may be related to the different mechanisms of translation initiation control.

The discovery of molecular signalling machines such as Ras nanoclusters, spatial activity gradients and flexible network circuitries involving transcriptional feedback, are beginning to reveal the design principles of spatiotemporal organization that are crucial for signalling network function and cell fate decisions.