Deubiquitinase-targeting chimeras for targeted protein stabilization

Shotgun proteomics uses liquid chromatography-tandem mass spectrometry to identify proteins in complex biological samples. We describe an algorithm, called Percolator, for improving the rate of confident peptide identifications from a collection of tandem mass spectra. Percolator uses semi-supervised machine learning to discriminate between correct and decoy spectrum identifications, correctly assigning peptides to 17% more spectra from a tryptic Saccharomyces cerevisiae dataset, and up to 77% more spectra from non-tryptic digests, relative to a fully supervised approach.

One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.

New biological tools provide new techniques to probe fundamental biological processes. Here we describe the burgeoning field of Proteolysis Targeting Chimera (PROTACs) which are capable of modulating protein concentrations at a post-translational level by co-opting the Ubiquitin-Proteasome System. We describe the PROTAC technology, its application to drug discovery and provide examples where PROTACs have enabled novel biological insights. Furthermore, we provide a workflow for PROTAC development and use as well as a discussion of the benefits and issues associated with PROTACs. Finally, we compare PROTAC mediated protein level modulation with other technologies such as RNA interference and genome editing.