Protein dynamics analysis identifies candidate cancer driver genes and mutations in TCGA data.

Recently, it has been showed that cancer missense mutations selectively target the neighborhood of hinge residues, which are key sites in protein dynamics. Here, we show that this approach can be extended to find previously unknown candidate mutations and genes. To this aim, we developed a computational pipeline to detect significantly enriched three-dimensional (3D) clustering of missense mutations around hinge residues. The hinge residues were detected by applying a Gaussian network model. By systematically analyzing the PanCancer compendium of somatic mutations in nearly 10 000 tumors from the Cancer Genome Atlas, we identified candidate genes and mutations in addition to well known ones. For instance, we found significantly enriched 3D clustering of missense mutations in known cancer genes including CDK4, CDKN2A, TCL1A, and MAPK1. Beside these known genes, we also identified significantly enriched 3D clustering of missense mutations around hinge residues in PLA2G4A, which may lead to excessive phosphorylation of the extracellular signal-regulated kinases. Furthermore, we demonstrated that hinge-based features improves pathogenicity prediction for missense mutations. Our results show that the consideration of clustering around hinge residues can help us explain the functional role of the mutations in known cancer genes and identify candidate genes.

Targeted degradation of the enhancer lysine acetyltransferases CBP and p300.

The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. Small molecule inhibitors that target some of these domains have been developed; however, they cannot completely ablate p300/CBP function in cells. Here we describe a chemical degrader of p300/CBP, dCBP-1. Leveraging structures of ligand-bound p300/CBP domains, we use in silico modeling of ternary complex formation with the E3 ubiquitin ligase cereblon to enable degrader design. dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drives MYC oncogene expression. As an efficient degrader of this unique class of acetyltransferases, dCBP-1 is a useful tool alongside domain inhibitors for dissecting the mechanism by which these factors coordinate enhancer activity in normal and diseased cells.

Protein dynamics analysis reveals that missense mutations in cancer-related genes appear frequently on hinge-neighboring residues.

Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer-related genes selectively target hinge-neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer-related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model. We then showed that missense mutations are significantly enriched on hinge-neighboring residues in oncogenes and tumor suppressor genes. We observed that several oncogenes (eg, MAP2K1, PTPN11, and KRAS) and tumor suppressor genes (eg, EZH2, CDKN2C, and RHOA) strongly exhibit this phenomenon. This study highlights and rationalizes the functional importance of missense mutations on hinge-neighboring residues in cancer.