Adam Frankel

Associate Professor

Research Interests

Protein Biochemistry
arginine methylation
post-translational modifications
Biological and Biochemical Mechanisms
Organic Molecules and Biomolecules
Bioactive Molecules
Chemical Biology
drug discovery
Target Engagement
Amino acids

Relevant Thesis-Based Degree Programs

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
I am interested in and conduct interdisciplinary research.
I am interested in working with undergraduate students on research projects.


Master's students
Doctoral students

"Methylation Dynamics in Cellular Processes" in the Frankel lab. 

"Overcoming Dihydrofolate Reductase Inhibitor Resistance Using Pyrimethamine-inspired Proteolysis Targeting Chimeras" with Drs. Brent Page and Karla Williams.

The ideal applicant should have a passion for and solid background in protein biochemistry, chemical biology, and bioorganic chemistry, as well as possess excellent writing and soft skills. 

I am open to hosting Visiting International Research Students (non-degree, up to 12 months).

Complete these steps before you reach out to a faculty member!

Check requirements
  • Familiarize yourself with program requirements. You want to learn as much as possible from the information available to you before you reach out to a faculty member. Be sure to visit the graduate degree program listing and program-specific websites.
  • Check whether the program requires you to seek commitment from a supervisor prior to submitting an application. For some programs this is an essential step while others match successful applicants with faculty members within the first year of study. This is either indicated in the program profile under "Admission Information & Requirements" - "Prepare Application" - "Supervision" or on the program website.
Focus your search
  • Identify specific faculty members who are conducting research in your specific area of interest.
  • Establish that your research interests align with the faculty member’s research interests.
    • Read up on the faculty members in the program and the research being conducted in the department.
    • Familiarize yourself with their work, read their recent publications and past theses/dissertations that they supervised. Be certain that their research is indeed what you are hoping to study.
Make a good impression
  • Compose an error-free and grammatically correct email addressed to your specifically targeted faculty member, and remember to use their correct titles.
    • Do not send non-specific, mass emails to everyone in the department hoping for a match.
    • Address the faculty members by name. Your contact should be genuine rather than generic.
  • Include a brief outline of your academic background, why you are interested in working with the faculty member, and what experience you could bring to the department. The supervision enquiry form guides you with targeted questions. Ensure to craft compelling answers to these questions.
  • Highlight your achievements and why you are a top student. Faculty members receive dozens of requests from prospective students and you may have less than 30 seconds to pique someone’s interest.
  • Demonstrate that you are familiar with their research:
    • Convey the specific ways you are a good fit for the program.
    • Convey the specific ways the program/lab/faculty member is a good fit for the research you are interested in/already conducting.
  • Be enthusiastic, but don’t overdo it.
Attend an information session

G+PS regularly provides virtual sessions that focus on admission requirements and procedures and tips how to improve your application.



These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.

Great Supervisor Week Mentions

Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.


Thank you so much, Adam, for your friendly supervision during the last years!!

Nelson Gorrin (2019)


Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Mechanistic investigations of protein arginine N-methyltransferases and elucidation of their implications in the yeast stress response (2021)

Protein arginine N-methyltransferases (PRMTs) catalyze the transfer of methyl groups from the methyl donor S-adenosyl-L-methionine (SAM) to polypeptide substrates. PRMTs are conserved among eukaryotes and many of their biological roles, including transcriptional regulation, DNA repair, and RNA processing, have been well elucidated. Another emerging research area is their role in stress pathways. Because of their significance in biological processes, PRMTs are promising drug targets for many human diseases. Knowledge of an enzyme’s kinetic mechanism and roles in cellular pathways can contribute to effective design of PRMT inhibitors. The purpose of this project was to examine how PRMTs bind to and methylate their substrates, and explore their roles in the stress response using Saccharomyces cerevisiae as a model organism. Using a combination of steady-state enzyme kinetics and biophysical assays, including differential scanning fluorimetry (DSF), we show that the predominant mammalian PRMT binds its substrates in a sequential manner where target substrate binding follows cofactor binding. By using knockout strains, we demonstrate that methylarginines are expelled from cells undergoing stress and that methylarginine expulsion is driven by autophagy. Further, we demonstrate that yeast do not take up methylarginines from their environment because methylarginines can inhibit nitric oxide production which is important for long-term cell survival under stressful growth conditions. Last, through studying in vitro methylation of yeast lysates using recombinantly expressed enzymes, we identify putative yeast methyltransferase Ynl092wp as a protein histidine N-methyltransferase that binds its substrates using a sequential mechanism and predict that Ykl162cp is an RNA methyltransferase. Here, we use a novel approach to examine the PRMT binding mechanism and we demonstrate that this novel technique is applicable to other enzyme families. Further, we demonstrate how yeast cells can evade cell toxicity by controlling methylarginine flux. Therefore, the research described herein encompasses the full importance and impact of PRMTs and their substrates in eukaryotic biological pathways.

View record

Searching for Inhibitors of the Protein Arginine Methyl Transferases: Synthesis and Characterisation of Peptidomimetic Ligands (2016)

Within the last two decades research in the field of epigenetics has increased significantly as targeting the epigenetic enzymes has the potential to alter the transcription of genes. Aberrant regulation of transcription is seen in several disease states, and drugs targeting the epigenetic histone deacetylases and DNA methylases are already marketed for cancer treatment. The Protein Arginine Methyl Transferases (PRMTs) belong to an epigenetic enzyme family that is upregulated in several cancers. However, currently no inhibitors of the PRMTs have been marketed. In this thesis several peptidomimetic strategies were utilised to modify the tryptophan residues in two peptide leads in order to discover new inhibitors of the PRMTs. One of these strategies involved constraining the side chain indole of tryptophan to the peptide backbone, thus producing a seven membered azepinone mimetic, Aia. The peptidomimetic efforts resulted in a structure-activity relationship study from which a constrained peptidomimetic containing two Aias was discovered to be a low micromolar inhibitor of several PRMTs. To characterise the inhibitor the conformation of the inhibitor was examined using solution-phase NMR and was shown to display an interesting turn-structure. The original peptide lead was fluorescently tagged and investigated in a cellular setting, but did not reveal any PRMT-specific localisation.In an effort to study the binding of the discovered inhibitor with the PRMTs, protein expression in E. coli and purification was performed. This resulted in the optimisation of PRMT6 purification in order to obtain highly pure PRMT6 for isothermal titration calorimetry (ITC) studies. Unfortunately these ITC studies were unsuccessful.Furthermore, as the constrained tryptophan mimetic had proven very useful in the peptidomimetic inhibitors of the PRMTs, we attempted to synthesise a lysine/arginine dipeptide mimetic using aziridine chemistry.

View record

The PRMT response to inflammation: substrate methylation and alternative splicing (2016)

Protein arginine N-methyltransferases (PRMTs) are a family of enzymes involved in signaling pathways and gene expression by methylating arginine residues of substrate proteins. PRMT2 has been demonstrated to play a role in the NF-κB signaling pathway. Moreover, our lab recently revealed association using proteomic techniques between PRMT2 and splicing factors including Src-associated in mitosis 68 kDa protein (SAM68) that mediates the alternative splicing of BCL-X involved in the NF-κB mediated inflammatory pathway. I wanted to investigate if the PRMT activity plays a role in response to inflammation under the treatment of inflammatory cytokine tumor necrosis factor-α (TNF-α) or pro-inflammatory bacterial lipopolysaccharide (LPS) in A549 cells. My proteomic experiments revealed that TNF-α and LPS cause similar changes to arginine methylation for proteins primarily involved in mRNA processing, RNA splicing, and nuclear transport, indicating that these two inflammatory stimuli share mutual downstream pathways involving methyltransferase activity. Among the proteins that showed hypermethylation upon treatment relative to control in mass spectrometry analysis, GAP SH3 domain-binding protein 2 (G3BP2) showed consistently in all three replicates on average a 1.5-fold increase in methylation at the R468 site in both TNF-α and LPS-treated cells. G3BP2 binds to IκB-α and prevents NF-κB translocation into the nucleus for subsequent signaling. G3BP2 methylation was necessary for signaling to occur in the Wnt/β-catenin signaling pathway. Methylation of G3BP2 might also have similar role in the inflammatory pathway that demands further study. Moreover, consistent with an inflammatory response, proteins particularly involved in innate immunity and viral response increased upon TNF-α treatment that could be related to the observed change in methylation of proteins involved in RNA processing. Our finding that PRMT2 interacts with SAM68, prompted me to investigate the potential role of PRMT2 in BCL-X alternative splicing. I found that reduced expression of PRMT2 by siRNA caused a decrease in the BCL-X(L)/BCL-X(s) ratio, suggesting that PRMT2 may contribute to BCL-X alternative splicing. This effect was replicated in TNF-α or LPS stimulated cells when PRMT2 expression was reduced by shRNA, and reversed when PRMT2 expression was increased. These results indicate that PRMT2 may play a role during inflammation in alternative splicing regulation.

View record

Oligomerization dependent enzyme kinetics and mechanistic characterization of type I protein arginine n-methytransferases (2013)

Protein arginine N-methyltransferases (PRMTs) constitute a family of post-translationalmodifying enzymes that modulate protein-protein interactions via the addition of methyl groupsto arginine residues in protein substrates (1). PRMTs have been demonstrated to homooligomerizevia a dimerization arm that binds with the outer surface of the S-adenosyl-Lmethionine(AdoMet) binding domain (2-5). In this body of work, I have demonstrated andquantified in vitro the strength of homodimerization for PRMT1 and PRMT6 and demonstratedthat saturating concentrations of S-adenosyl-L-methionine (AdoMet) or S-adenosyl-Lhomocysteine(AdoHcy) respectively strengthen or weaken this interaction. This findingsupports an ordered bisubstrate mechanism in which AdoMet binding promotes formation of thecomplete peptide-substrate binding groove through dimerization, and AdoHcy generationpromotes dissociation of the dimeric complex and turnover of substrate.A kinetic study using HIV Tat peptides revealed oligomerization-dependent kineticpatterns with these substrates. Kinetic experiments were initially performed on HIV Tat peptidewith novel ωN-substitutions to probe their ability to inhibit PRMT1, 4 and 6. It was found thatthese Tat-peptides act as substrate inhibitors for both PRMT1 and PRMT6 and that this substrateinhibition was mitigated as the enzyme concentration increased. A model was proposed thatrepresents activity as the sum of each ordered oligomer in solution, with the monomer beinguniquely susceptible to substrate inhibition.Diverging from strictly oligomerization effects, R1 fibrillarin-like peptide containing asingle arginine was substituted to alter the pKa of the terminal guanidino group to better probethe physicochemical properties that control methyltransfer. Surprisingly, hydroxyl substitutedR1 peptide demonstrated an enhanced catalytic constant with PRMT1. MS and MS² experiments demonstrate that only monomethylation occurs on substituted arginines with PRMT1, and that this addition is asymmetric. PRMT1 D51N, a catalytically compromised mutant, revealed the kcat as rate limiting in the presence of D₂O, and electrostatic potential maps indicate that deprotonation of hydroxyl substituted arginine produces a strong nucleophile capable of enhanced methyltransfer.Altogether, these studies support water mediated, ordered bisubstrate mechanism in which oligomerization modulates activity. Substrate inhibition and active site chemistry were investigated using novel chemically substituted peptide probes that highlight trends beyond what site-directed mutagenesis can reveal alone.

View record

Insights into a heteronomic protein arginine N-methyltransferase complex (2012)

Protein arginine N-methyltransferases (PRMTs) act in signaling pathways and geneexpression by methylating arginine residues within target proteins. PRMT1 is responsible formost cellular arginine methylation activity and can work independently or in collaboration withother PRMTs. In this Ph.D. thesis I demonstrated an interaction between PRMT1 and -2 usingco-immunoprecipitation and bimolecular fluorescence complementation (BiFC). As a result ofthis interaction, PRMT2 stimulated PRMT1 methyltransferase activity, affecting its apparentVmax and Km values in vitro, and increasing the production of methylarginines in cells. Activesite mutations and regional deletions on PRMT1 and -2 were also investigated, whichdemonstrated that complex formation required full-length, active PRMT1. However, theinteraction between PRMT1 and -2 proved insensitive to methylation inhibition in the absence ofthe PRMT2 Src homology 3 (SH3) domain, which suggests that the PRMT2 SH3 domain maymediate this interaction between PRMT1 and -2 in a methylation-dependent fashion.The role of the PRMT2 SH3 domain was investigated through screening for its associatedproteins using GST-pull down assays followed by LC-MS/MS proteomic analysis. The result ofthis study revealed associations of the PRMT2 SH3 domain with at least 29 splicing-relatedproteins, suggesting a potential role of PRMT2 in regulating pre-mRNA processing and splicing.The interaction between PRMT2 and the Src substrate associated in mitosis of 68 kDa (Sam68)possibly through the PRMT2 SH3 domain was demonstrated using co-immunoprecipitation.Additionally, immunofluorescence results present herein imply that the PRMT2 SH3 domaincould affect Sam68 sub-cellular localization in hypomethylated HeLa cells. The biological functions of PRMT2 and the PRMT1/2 heteromeric complex were exploredby pursuing the identity of associated proteins common to both PRMT1 and -2 using massspectrometry proteomics. Approximately 50% of the identified protein hits have reported rolesin controlling gene expression, while other hits are involved in diverse cellular processes such asprotein folding, degradation, and metabolism. Importantly, three novel PRMT2 binders, p53,promyelocytic leukemia protein (PML), and extra eleven nineteen (EEN) were uncovered,suggesting that PRMT2 could participate in regulation of transcription and apoptosis throughPRMT2-protein interactions.

View record

Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Alternative approaches to the study of ligand-induced protein stability : facilitating the development of novel target engagement and drug binding assays (2023)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

View record

Evaluation of Ginsenosides in Transactivation and Transrepression of Human Glucocorticoid Receptor Alpha (2016)

Ginsenosides are pharmacologically active compounds in ginseng, a medicinal herb that is highly valued and widely consumed. They are reported to have diverse effects, including neuromodulation, anticancer, and immunomodulation. Glucocorticoid receptor (GR) is a nuclear receptor involved in transcriptional regulation of genes in numerous important physiological processes, such as stress-related homeostasis, gluconeogenesis, bone remodeling, and anti-inflammation. Previous research suggested ginsenosides as agonists of rodent GRα. Studies on human GRα (hGRα) mainly focused on a single ginsenoside and its effect on either hGRα-mediated transactivation or transrepression. However, only a few ginsenosides (compound K, Rh1, Rh2, Re, Rg1) were examined and it is not known whether ginsenosides activate hGRα in an analog-selective manner. In this study, seven protopanaxadiol (PPD)-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and five protopanaxatriol (PPT)-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) were investigated to determine whether they act as functional ligands of hGRα for both its transactivation and transrepression activity. In vitro time resolved-fluorescence resonance energy transfer (TR-FRET) competitive ligand-binding assay revealed that ginsenosides can weakly bind to the ligand-binding domain of hGRα. Among the selected ginsenosides, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited strongest binding to the receptor. Dual-luciferase reporter gene assays employing firefly luciferase reporter vectors carrying either glucocorticoid response element or NF-κB response element were conducted in human colon adenocarcinoma cells (LS180). None of the ginsenosides increased or attenuated hGRα-mediated transactivation or transrepression activity. Furthermore, hGRα target gene (hTAT and hCBG) expression was studied in human hepatocellular carcinoma cells (HepG2) and quantified by real-time PCR. The data indicated that ginsenoside Rh2 did not influence hGRα target gene expression. In summary, among all PPD-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and PPT-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) tested, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited stronger binding to hGRα-LBD, while others could only bind weakly. Nevertheless, none of the ginsenosides could modulate hGRα activity or affect target gene expression. Therefore, these ginsenosides are not functional ligands of hGRα in LS180 and HepG2 cells.

View record

The Search for Novel Inhibitors of Coactivator-Associated Arginine Methyltransferase 1 (2015)

Coactivator-associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family of enzymes, and is also known as PRMT4. PRMTs catalyse the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to the side chain of arginine residues in substrate proteins. The dysregulation of CARM1 contributes to the onset and progression of breast and prostate cancer. For this reason, CARM1 is a target for inhibition, yet CARM1 inhibitors to date either lack selectivity or fail to show anti-proliferative effects in cells. This work aims to identify novel small molecules that can be further developed to inhibit CARM1 activity in cancer cells.Using the crystal structure (2Y1X) of the CARM1 catalytic domain in complex with CMPD-2 and S-adenosyl-L-homocysteine as a model for downstream screening, a computer-aided drug discovery and design (CADD) pipeline was developed, enabling docking to identify novel inhibitors. Over 76,600 compounds alongside known CARM1 inhibitors were screened using the industry standard proprietary software suite Accelrys Discovery Suite 4.5®. LibDock and CDOCKER algorithms were deployed independently and in series. Subsequently, a P81 filter-binding assay assessed the top hits from the in silico screening for CARM1 inhibition in vitro to generate IC50 values. A lead CARM1 inhibitor, Diamine 12 was used as a positive control, which scored highly with LibDock and CDOCKER and had an IC50 value of 1.3±1 µM with the P81 filter-binding assay. Top-ranked hits identified using Accelrys® showed some binding interactions in the arginine-binding cavity yet little to no activity in vitro. The work here fundamentally addresses the development of a workflow that provides a platform for discovery consisting of in vitro and in silico screening methods. Future work will involve expanding on the findings here to identify novel CARM1 inhibitors to be developed into therapeutic agents for the treatment of breast and prostate cancers.

View record


Current Students & Alumni

This is a small sample of students and/or alumni that have been supervised by this researcher. It is not meant as a comprehensive list.

If this is your researcher profile you can log in to the Faculty & Staff portal to update your details and provide recruitment preferences.


Sign up for an information session to connect with students, advisors and faculty from across UBC and gain application advice and insight.