Reviews & Analysis

Despite their potential importance as therapeutic targets, the initial events in neurodegenerative diseases are poorly understood. Emerging evidence suggests that presynaptic dysfunction might be an early event in these pathologies, and three papers now link dysregulation of SNARE protein levels and function caused by the absence of synuclein or cysteine string protein (CSP) to activity-dependent neurodegeneration.

Whether class V myosins can work as point-to-point transporters in animal cells is highly debated. Myosin-Va is now shown to function as a point-to-point transporter that pulls the endoplasmic reticulum (ER) into dendritic spines, with important consequences for dendritic development and cerebellar motor learning.

Substrate specificity in ubiquitylation is conferred by ubiquitin ligases (E3s). Now, several ways that E3s can interact to mediate ubiquitylation are illustrated for Ubr1 (a RING finger E3) and Ufd4 (a HECT domain E3), in Saccharomyces cerevisiae. These interactions and the related concept of E4 activity are discussed.

The histone H3 variant CENP-A defines centromeric chromatin, but it has been unclear how CENP-A is stably maintained at centromeres. It has now been shown that the CENP-A licensing factor HsKNL2 and the small GTPases activating protein MgcRacGAP cooperate to promote the stability of newly loaded CENP-A at centromeres.

Cytoplasmic dynein drives vesicular transport from the periphery to the cell body of neurons. Missense mutations in the dynein tail domain cause neurodegenerative disease in mouse models. New data on the effect of one such dynein mutation provide insight into the intramolecular communication and flexible stepping of this essential cellular motor.

Cells sense and respond to physical stresses through mechanotransduction, a process that converts mechanical stimuli into biochemical signals. The bending of primary cilia has now been shown to modulate TOR signalling to negatively regulate cell size.

Changes in chromatin structure are a conserved hallmark of ageing, and the mechanism driving these changes, as well as their functional significance, are heavily investigated. Loss of core histones is now observed in aged cells and may contribute to this phenomenon. Histone loss is coupled to cell division and seems to be triggered by telomeric DNA damage.

The contribution and order of polarity complexes and vesicular trafficking events during lumen formation remains obscure. Now, lumenogenesis in MDCK cell cysts is shown to require a Rab11a–Rabin8–Rab8a network that recruits Sec15A and Cdc42 and that promotes apical exocytosis by enlisting the Par complex and Sec8–Sec10 to an early apical membrane initiation site.

Protein S-nitrosylation is thought to be mediated primarily by nitric oxide synthases. S-nitrosylated GAPDH is now shown to function within signal transduction cascades as a nuclear nitrosylase. Along with other recent demonstrations of regulated protein–protein transnitrosylation, these findings point to a new mechanism of signal transduction with transformative implications for nitric oxide biology and redox signalling.

Transcriptional noise has an important role in generating diversity in cellular populations that are seemingly identical. As this noise stems from the inherent stochasticity of gene expression, it has been unclear whether it is directly controlled. Dig1, a regulator of the budding yeast mating pathway, is now shown to prevent transcriptional noise by regulating the spatial organization of downstream gene targets.

The epithelial–mesenchymal transition (EMT) occurs in pre-metastatic cancer cells and is also associated with the acquisition of stem-cell-like characteristics. A molecular link between EMT and stemness now emerges with the finding that Bmi1, a polycomb protein that promotes self-renewal of certain stem-cell populations, is a direct transcriptional target of the EMT inducer, Twist1.

Distinct stem-cell populations are known to reside in hypoxic niches during development and postnatal life. Hypoxia-inducible transcription factors (HIFs) directly regulate the Wnt/β-catenin pathway to ensure the maintenance of both adult and embryonic stem cells.

Pumilio proteins PUM1 and PUM2 are shown to regulate microRNA-dependent gene silencing by induction of a conformational switch in the 3′ untranslated region of p27 mRNA. This conformational change is required for efficient microRNA-mediated repression of this cell-cycle regulator in rapidly proliferating cells.

It has been proposed that the spindle assembly checkpoint detects both unattached kinetochores and lack of tension between sister kinetochores when sister chromatids are not attached to opposite spindle poles. However, here we argue that there is only one signal — whether kinetochores are attached to microtubules or not — and this has implications for our understanding of both chromosome segregation and the control of genomic stability.

Mounting evidence suggests that keratin post-translational modifications are crucial for many cellular processes. Now, keratin 18 modified by the addition of an O-linked N-acetylglucosamine residue is shown to be as a critical effector of stress-responsive Akt signalling, providing an important link between keratin glycosylation and cell survival.

Kinetochores link microtubules to DNA and provide force critical for chromosome segregation in mitosis. New data show that kinetochores are not necessary for acentrosomal meiotic chromosome segregation in Caenorhabditis elegans. Instead, CLS-2 (CLASP) generates a mid-zone bundle of microtubules that are suggested to act in pushing the chromosomes apart.