Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of β-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a β-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates β-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.

The human genome encodes a family of nine protein arginine methyltransferases (PRMT1-9), which members can catalyze three distinct types of methylation on arginine residues. Here, we identify two spliceosome-associated proteins – SAP145 and SAP49 – as PRMT9 binding partners, linking PRMT9 to U2snRNP maturation. We show that SAP145 is methylated by PRMT9 at arginine 508, which takes the form of monomethylated arginine (MMA) and symmetrically dimethylated arginine (SDMA). PRMT9 thus joins PRMT5 as the only mammalian enzymes capable of depositing the SDMA mark. Methylation of SAP145 on Arg508 generates a binding site for the Tudor domain of the Survival of Motor Neuron (SMN) protein, and RNA-seq analysis reveals gross splicing changes when PRMT9 levels are attenuated. These results identify PRMT9 as a non-histone methyltransferase that primes the U2snRNP for interaction with SMN.

Histone tail post-translational modification results in changes in cellular processes, either by generating or blocking docking sites for histone code readers or by altering the higher order chromatin structure. H3K4me3 is known to mark the promoter regions of active transcription. Proteins bind H3K4 in a methyl-dependent manner and aid in the recruitment of histone-remodeling enzymes and transcriptional cofactors. The H3K4me3 binders harbor methyl-specific chromatin binding domains, including plant homeodomain, Chromo, and tudor domains. Structural analysis of the plant homeodomains present in effector proteins, as well as the WD40 repeats of WDR5, reveals critical contacts between residues in these domains and H3R2. The intimate contact between H3R2 and these domain types leads to the hypothesis that methylation of this arginine residue antagonizes the binding of effector proteins to the N-terminal tail of H3. Here we show that H3 tail binding effector proteins are indeed sensitive to H3R2 methylation and that PRMT6, not CARM1/PRMT4, is the primary methyltransferase acting on this site. We have tested the expression of a select group of H3K4 effector-regulated genes in PRMT6 knockdown cells and found that their levels are altered. Thus, PRMT6 methylates H3R2 and is a negative regulator of N-terminal H3 tail binding.The tight packing of DNA into chromatin creates a need for mechanisms to relax chromatin and expose DNA for transcription, replication, and DNA repair (1). One of the mechanisms used by the cell to access DNA is the post-translational modification of histone tails. Specifically, methylation of histone tails generates a docking site for effector proteins, which aid in the recruitment of other enzymes necessary for the function at hand. In general, methylation of histone residues lysines 4 and 36 on H3 are correlated with active gene regions, whereas methylation of lysines 9 and 27 on H3 is correlated with repressed gene regions, although exceptions exist (2). The domain types that bind histone tails include the Chromodomain, tudor domains, MBT domains, WD40 repeats, and PHD 5 fingers (3-5).Recently, two groups reported that select PHD fingers have the propensity to bind trimethyl lysine 4 on H3 (6, 7). The structures further showed important aromatic residues in the PHD that cage the methylated lysine but also revealed critical contacts made between the arginine at the second position of the H3 tail and the PHD (8, 9). During this same time, the WD40 domain of WDR5 was reported to complex with the H3 tail (10). The structure of the WD40 repeats of WDR5 revealed arginine 2 of H3, and not lysine 4, buried within the donut hole of the large domain (11,12). Specifically, four amino acids in WDR5 critically interact with arginine 2 (11). In addition, the tudor domains of JMJD2A also bind in an H3K4me3-dependent manner, and again, the H3R2 residue forms critical interactions with an Asp residue of one of the tudor domains (13). The analysis of the structures of these three different domain types bound to t...

The burden of AF among Asian patients is increasing. Although the overall risks of cardiovascular events and death following AF onset have decreased over a decade, the event rates are still high. Optimized management of any associated comorbidities should be part of the holistic management approach for patients with AF.