Erratum: Addendum: A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1 (Nature chemical biology (2016) 12 3 (180-187))

[No abstract available

A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K d of â ∼1/4100 nM for each, and is 6-to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects

Investigating the record of Permian climate change from argillaceous sedimentary rocks, Oman

A standard method for the analysis of carbon isotope composition of bulk organic matter (δ13Cbulk) in palaeoenvironmental and stratigraphic studies of sedimentary basins associated with hydrocarbons is suggested. This method includes the removal of interstitial hydrocarbon within the sediments, which is shown to have a negative effect on δ13C. Using the method, a δ13Cbulk trend (c. −21 to −24‰) was found within the Lower Permian Al Khlata and lower Gharif formations of Thuleilat-16 and -42 well sections, south Oman. Palaeontological and sedimentological evidence indicates considerable palaeoenvironmental change, from a cold climate lowland fern flora and upland primitive conifer flora low in the sequence, to a lowland cycad-like and upland glossopterid or other gymnospermous flora higher in the sequence. The lithologies range from glacial diamictite at the base to calcrete horizons and redbeds at the top. It is therefore likely that the δ13Cbulk trend is related to palaeoenvironmental change

MYC protein interactors in gene transcription and cancer

The transcription factor and oncoprotein MYC is a potent driver of many human cancers and can regulate numerous biological activities that contribute to tumorigenesis. How a single transcription factor can regulate such a diverse set of biological programmes is central to the understanding of MYC function in cancer. In this Perspective, we highlight how multiple proteins that interact with MYC enable MYC to regulate several central control points of gene transcription. These include promoter binding, epigenetic modifications, initiation, elongation and post-transcriptional processes. Evidence shows that a combination of multiple protein interactions enables MYC to function as a potent oncoprotein, working together in a \u2018coalition model\u2019, as presented here. Moreover, as MYC depends on its protein interactome for function, we discuss recent research that emphasizes an unprecedented opportunity to target protein interactors to directly impede MYC oncogenesis

Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40

The huntingtin (HTT) protein plays critical roles in numerous cellular pathways by functioning as a scaffold for its many interaction partners and HTT knock out is embryonic lethal. Interrogation of HTT function is complicated by the large size of this protein so we studied a suite of structure-rationalized subdomains to investigate the structure-function relationships within the HTT-HAP40 complex. Protein samples derived from the subdomain constructs were validated using biophysical methods and cryo-electron microscopy, revealing they are natively folded and can complex with validated binding partner, HAP40. Derivatized versions of these constructs enable protein-protein interaction assays in vitro, with biotin tags, and in cells, with luciferase two-hybrid assay-based tags, which we use in proof-of-principle analyses to further interrogate the HTT-HAP40 interaction. These open-source biochemical tools enable studies of fundamental HTT biochemistry and biology, will aid the discovery of macromolecular or small-molecule binding partners and help map interaction sites across this large protein