Debler Research
Contact
1020 Locust Street
JAH 411F
Philadelphia, PA 19107
Highlighted Publications
Farkas M, Hashimoto H, Resnick-Silverman L, Bi Y, Davuluri RV, Manfredi JJ, Debler EW, McMahon SB. Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates. Nat Commun. 12:484, 2021.
We deciphered the mechanism that governs selective engagement of the tumor suppressor p53 – a master regulatory transcription factor that integrates stress response pathways by triggering different cell fates – with distinct response elements, thereby answering the fundamental and long-standing question of how p53 can turn on distinct gene expression programs
Frisbie VS, Hashimoto H, Xie Y, De Luna Vitorino FN, Baeza J, Nguyen T, Yuan Z, Garcia BA, Debler EW. Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids. Nat Commun 15:2467, 2024.
We discovered that the nucleosomal histone lysine methyltransferases DOT1A and DOT1B of the early-branched eukaryote Trypanosoma brucei exhibit distinct methylation kinetics and substrate preferences, enabling them to mediate efficient H3K76 tri-methylation cooperatively and suggesting why T. brucei and related eukaryotes have evolved two DOT1 enzymes.
Farkas M, Hashimoto H, Resnick-Silverman L, Bi Y, Davuluri RV, Manfredi JJ, Debler EW, McMahon SB. Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates. Nat Commun. 12:484, 2021.
We deciphered the mechanism that governs selective engagement of the tumor suppressor p53 – a master regulatory transcription factor that integrates stress response pathways by triggering different cell fates – with distinct response elements, thereby answering the fundamental and long-standing question of how p53 can turn on distinct gene expression programs
Jain K, Warmack RA, Debler EW, Hadjikyriacou A, Stavropoulos P, and Clarke SG. Protein Arginine Methyltransferase Product Specificity is Mediated by Distinct Active-Site Architectures. J. Biol. Chem., 291:18299, 2016
We converted a protein arginine methyltransferase, which only produces monomethylarginine, into enzymes capable of asymmetric and symmetric dimethylarginine formation, providing a structural basis and a general model for product specificity in PRMTs.
Debler EW, Jain K, Warmack RA, Feng Y, Clarke SG, Blobel G, and Stavropoulos P. A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase. Proc. Natl. Acad. Sci. USA, 113:2068, 2016
Structural and biochemical analyses of a protein arginine monomethyltransferase provide insights into the mechanism of action and the exquisite product specificity of this important class of enzymes, linked to a variety of diseases.
Schulz D, Mugnier M, Paulsen EM, Kim HS, Chung CW, Tough DF, Rioja D, Prinjha RK, Papavasiliou FN, and Debler EW. Bromodomain proteins contribute to maintenance of bloodstream form stage identity in the African trypanosome. PLOS Biol., 13: e1002316, 2015
We reveal an unexpected role of trypanosome bromodomains in maintenance of life-cycle stage identity and establish the druggability of this pathway with a small-molecule inhibitor, delineating a novel effective treatment for African sleeping sickness.
Recent Publications
Structural enzymology of cholesterol biosynthesis and storage
Coil-to-α-helix transition at the Nup358-BicD2 interface activates BicD2 for dynein recruitment
A Quantitative Model for BicD2/Cargo Interactions
A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase
The Structure of the nuclear pore complex
Structure of a trimeric nucleoporin complex reveals alternate oligomerization states
Structural and functional analysis of Nup120 suggests ring formation of the Nup84 complex
Nuclear transport comes full circle