Reviews & Analysis

Recent work revealed new insights into the temporal regulation of G1–S cell cycle transcription, during proliferation and in response to activation of the DNA replication checkpoint. This has established the importance of G1–S transcription for both cell cycle progression and the maintenance of genome stability.

The ability of integrins to link the extracellular environment to intracellular networks enables cells to respond to chemical and physical cues. Insight has been gained into how talins and kindlins, two families of FERM-domain proteins that bind the cytoplasmic tail of integrins, mediate integrin activation and the cellular processes that depend on this.

Lineage-tracing and genetic labelling technologies, combined with statistical analyses of cell proliferation and clonal fate, provide powerful tools to study the mechanisms and dynamics of stem and progenitor cell fate determination in development and disease.

The adult mammalian heart has limited potential for regeneration and repair. Progress has been made in elucidating the cellular processes and regulatory mechanisms involved in heart growth and development, and this can be exploited to restore function in the injured adult heart.

The mechanisms that regulate miRNA stability and the generation of distinct miRNA isoforms are beginning to be elucidated. Better understanding of how such miRNAs mediate gene expression control will require quantitative analyses that dissect different models of miRNA function.

Cofilin severing activity can generate free actin filament ends that are accessible for F-actin polymerization and depolymerization. The combination of structural data for filament severing with recently discovered mechanisms for cofilin activation in migrating cells is increasing our understanding of how cofilin activity affects cell behaviour.

The founding member of the Hedgehog (HH) family of secreted proteins was cloned two decades ago. The mechanism of HH signalling is incomplete, but insight has been gained into the function of lipidation in ligand secretion and transport, as well as into key components of the signalling pathway.

Traditionally, the integrin activity status was thought to be regulated by activators (talin and kindlin), with integrins passively adopting an inactive state. However, it is now emerging that the integrin activity state is dynamically regulated, with inactivators (SHARPIN, ICAP1 and filamin) having a key role in dampening integrin function in different cellular contexts.

The distinct organization of the endoplasmic reticulum (ER)–Golgi interface across species reflects variation in the mechanisms that control transport between these organelles. Continued comparative analyses of this interface should help to elucidate the ways that ER–Golgi trafficking control can be adapted to meet cell type-specific needs.

Subsets of mammalian adult stem cells reside in a reversible quiescent state. Recent studies of epigenetic, transcriptional and post-transcriptional events underlying quiescence suggest that this state is actively maintained by signalling pathways that keep cells poised for rapid activation, rather than this being a dormant state with minimal basal activity.

The methylation of cytosine bases in DNA has a key role in regulating transcription. It has recently been discovered that ten-eleven translocation (TET) proteins can reverse DNA methylation, refining our view of how changes in DNA methylation are coupled to different cellular processes.

Pluripotent stem cell lines differ in their capacity to differentiate into desired cell typesin vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within single clones. Characterizing such variations is important for the use of pluripotent stem cells in disease modelling and developmental processes and for their applications in regenerative medicine.

Through their role as substrate adaptors for S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) ubiquitin ligase complexes, F-box proteins control the degradation of a large number of proteins with wide-ranging functions. Studying the mechanisms of substrate recruitment by F-box proteins has increased our understanding of their dysregulation in disease and might lead to targeted therapies.

As well as degrading and recycling cellular waste, lysosomes are involved in secretion, plasma membrane repair, signalling and energy metabolism. The identification of transcription factor EB (TFEB) as a central regulator of lysosomal biogenesis and autophagy provides insight into how lysosomes adapt to environmental cues, and targeting TFEB may be a promising therapeutic strategy for modulating lysosomal function in disease.

Recent work on the structure and function of the RB protein revealed its multifunctionality in cancer and during normal physiology. Remarkably, additional tumour-suppressor functions have come to light, including new roles in cell cycle regulation, maintenance of genome stability and apoptosis.

The proliferating cell nuclear antigen (PCNA) processivity factor provides a central regulatory platform during DNA replication and associated processes, including DNA damage repair. The interaction of PCNA with many cellular proteins is key to this function and is subject to tight, multilayered control.

The ability of signal transduction pathways to directly modify chromatin provides a means for rapid, and potentially long-lived, responses to environmental cues. Understanding how these modifications are stored on chromatin, integrated and interpreted should provide insight into the short- and long-term control of gene expression.

Ataxia-telangiectasia mutated (ATM) is best known for its role in orchestrating the DNA damage response in response to double-strand breaks. However, it is now emerging that it is a far more versatile kinase, with roles in cell responses to other genotoxic stresses and in signalling pathways involved in cellular homeostasis.

During cell reprogramming and direct cell fate conversion, changes in somatic and pluripotent cell fates do not require the passage through a hierarchy of distinct cell fates that are proposed to occur during normal development and are consistent with the original Waddington model. Instead, a 'flat epigenetic disc' model might explain cell fate transitions during these processes.

All three domains of life – Bacteria, Archaea and Eukarya – have a proteostasis network that modulates protein folding in response to changes in the environment and to genetic variation. This proteostasis network has co-evolved with the proteome and is thought to play a part in driving evolution.