Mammalian kinetochores count attached microtubules in a sensitive and switch-like manner to control cell cycle progression

The Spindle Assembly Checkpoint (SAC) maintains genomic integrity by preventing anaphase until all kinetochores attach to the spindle. What specific signals are required for SAC satisfaction at mammalian kinetochores, and in what magnitude, are not well understood and central to understanding SAC signal processing and function. Here, we directly and independently tune candidate input signals – spindle forces and Hec1-microtubule binding – and map SAC outputs. By detaching microtubules from the spindle, we first demonstrate that the SAC does not respond to changes in spindle pulling forces. We then tune and fix the fraction of Hec1 molecules capable of microtubule binding, and interpret SAC output changes as coming from changes in binding, and not spindle forces. While the speed of satisfaction reduces with fewer attached microtubules, the kinetochore turns off the SAC even with few – approximately four – such microtubules. Thus, the mammalian kinetochore responds specifically to microtubule binding, and does so as a single, switch-like, sensitive unit. This may allow the kinetochore to rapidly react to attachments and maintain a robust response despite dynamic microtubule numbers.

Regulated Proteolysis in Bacteria

Regulated proteolysis is a vital process that affects all living things. Bacteria use energy-dependent AAA+ proteases to power degradation of misfolded and native regulatory proteins. Given that proteolysis is an irreversible event, specificity and selectivity in degrading substrates are key. Specificity is often augmented through the use of adaptors that modify the inherent specificity of the proteolytic machinery. Regulated protein degradation is intricately linked to quality control, cell-cycle progression, and physiological transitions. In this review, we highlight recent work that has shed light on our understanding of regulated proteolysis in bacteria. We discuss the role AAA+ proteases play during balanced growth as well as how these proteases are deployed during changes in growth. We present examples of how protease selectivity can be controlled in increasingly complex ways. Finally, we describe how coupling a core recognition determinant to one or more modifying agents is a general theme for regulated protein degradation.

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0–57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.