BACKGROUND AND OBJECTIVES: National initiatives have encouraged oral health training for family physicians and other nondental providers for almost 2 decades. Our national survey assesses progress of family medicine residency programs on this important health topic since our last survey in 2011. METHODS: Family medicine residency program directors (PDs) completed an online survey covering various themes including number of hours of oral health (OH) teaching, topics covered, barriers, evaluation, positive influences, and program demographics. RESULTS: Compared to 2011, more PDs feel OH should be addressed by physicians (86% in 2017 vs 79% in 2011), yet fewer programs are teaching OH (81% vs 96%) with fewer hours overall (31% vs 45% with 4 or more hours). Satisfaction with the competence of graduating residents in OH significantly decreased (17% in 2017 vs 32% in 2011). Program directors who report graduates being well prepared to answer board questions on oral health topics are more likely to have an oral health champion (P < 0.001) and report satisfaction with the graduates' level of oral health competency (Pandlt;0.001). Programs with an oral health champion, or having a relationship with a state or national oral health coalition, or having routine teaching from a dental professional are significantly more likely to have more hours of oral health curriculum (P < 0.001). CONCLUSIONS: Family medicine PDs are more aware of the importance of oral health, yet less oral health is being taught in residency programs. Developing more faculty oral health champions and connecting programs to dental faculty and coalitions may help reduce this educational void.

Protein arginine methyltransferase 5 (PRMT5) is a histone-modifying enzyme whose activity is aberrantly upregulated in various cancers and thereby contributes to a progrowth phenotype. Indeed, knockdown of PRMT5 leads to growth arrest and apoptosis, suggesting that inhibitors targeting this enzyme may have therapeutic utility in oncology. To aid the development of inhibitors targeting PRMT5, we initiated mechanistic studies geared to understand how PRMT5 selectively catalyzes the symmetric dimethylation of its substrates. Toward that end, we characterized the regiospecificity and processivity of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5), insect cell-expressed human PRMT5 (hPRMT5), and human PRMT5 complexed with methylosome protein 50 (MEP50), i.e., the PRMT5.MEP50 complex. Our studies confirm that arginine 3 is the only site of methylation in both histone H4 and H4 tail peptide analogues and that sites distal to the site of methylation promote the efficient symmetric dimethylation of PRMT5 substrates by increasing the affinity of the monomethylated substrate for the enzyme. Additionally, we show for the first time that both cPRMT5 and the hPRMT5.MEP50 complex catalyze substrate dimethylation in a distributive manner, which is assisted by long-range interactions. Finally, our data confirm that MEP50 plays a key role in substrate recognition and activates PRMT5 activity by increasing its affinity for protein substrates. In total, our results suggest that it may be possible to allosterically inhibit PRMT5 by targeting binding pockets outside the active site.

Protein arginine methyltransferases (PRMTs) have emerged as attractive therapeutic targets for heart disease and cancers. PRMT5 is a particularly interesting target because it is overexpressed in blood, breast, colon, and stomach cancers and promotes cell survival in the face of DNA damaging agents. As the only known member of the PRMT enzyme family to catalyze the formation of mono- and symmetrically dimethylated arginine residues, PRMT5 is also mechanistically unique. As a part of a program to characterize the mechanisms and regulation of the PRMTs and develop chemical probes targeting these enzymes, we characterized the substrate specificity, processivity, and kinetic mechanism of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5). In this report, we demonstrate that distal positively charged residues contribute to substrate binding in a synergistic fashion. Additionally, we show that cPRMT5 catalyzes symmetric dimethylation in a distributive fashion. Finally, the results of initial velocity, product, and dead-end inhibition studies indicate that cPRMT5 uses a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes. In total, these studies will guide PRMT5 inhibitor development and lay the foundation for studying how the activity of this medically relevant enzyme is regulated.