Dr. Arrowsmith received her PhD from the University of Toronto in 1987 and post-doctoral training at Stanford University. In 1991 she started her independent research program at the Ontario Cancer Institute investigating how transcription factors recognize DNA to regulate gene expression and cell growth.
- Epigenetics and Drug DiscoveryEpigenetics refers to heritable differences in phenotype that are due to mechanisms other than differences in DNA sequence. Epigenetics involves a dynamic interplay between DNA methylation, posttranslational modification of histones and other proteins, and noncoding RNA networks that control gene expression programs in normal and diseased cells.
Mutations in chromatin regulatory genes and alterations of the cellular epigenome are prevalent in most cancers. Post-translational modifications (PTMs) on histone proteins serve as docking sites for chromatin-associated proteins, which in turn dictate dynamic conversion between transcriptionally active or silent chromatin states. The combinatorial nature of these modifications establishes a "histone code" which serves to expand the information present in the DNA-sequence of the genetic code. Lysine methylation is the most complex mark, and it plays a pivotal role in heterochromatin formation, transcriptional regulation and X-chromosome inactivation. Mutations or aberrant expression of proteins containing these domains often leads to deregulation of histone lysine methylation, leading to various diseases, most notably, cancer.
We work with the Structural Genomics Consortium (SGC) to develop structure-based potent, selective, cell-active small molecule inhibitors of individual epigenetic regulatory proteins. These compounds, also referred to as chemical probes, are extremely valuable for understanding epigenetic signaling mechanisms in cells. Chemical probes are highly complementary to genetic methods and more closely mimic strategies for therapeutic translation. We are providing our epigenetic chemical probes as an Open Access resource to the biological research community to facilitate understanding of epigenetic mechanisms and to more rapidly identify and validate therapeutic targets for cancer and other diseases.
- p53, ubiquitin signaling, and cancerp53 protein plays a major role in maintaining the integrity of the genome. One of its major roles in normal cells is the induction of cell cycle arrest or apoptosis in response DNA damage, by activating or repressing transcription of genes involved in these processes. Inactivation of the tumor suppressor p53 through deletion, mutation or interaction with proteins is a key step in over half of all human cancers. We are particularly interested in understanding, at the atomic levels, how various cellular proteins interact with and regulate the function of p53. Some of the proteins we have characterized include Replication Protein A (RPA), Ubiquitin Specific Protease 7 (USP7), Cullin 7 (Cul7) and Pirh2. Results from these studies have provided insight into the molecular mechanism of p53 regulation via protein-protein and protein-peptide interactions.
Our work on ubiquitin-mediated regulation of p53 has led us to wider consideration of ubuquitylation pathways. Again in collaboration with the SGC we have studied proteins involved in chromatin ubiquitylation (UHRF1, UHRF2, Ring1b) and the entire E2 ubiquitin ligase and ubiquitin-like domain families.
- NMR spectroscopy and hybrid methods in structural biologyNMR spectroscopy and x-ray crystallography are the two common techniques used to determine the structure of proteins. We have developed NMR analysis resources such as ABACUS, a protocol that analyzes networks of J-correlated spectral peptide-linked peaks and NOE spectral peaks combined with a fragment monte carlo (FMC) procedure to sequence-specifically assign the backbone and side-chain resonances of proteins. To date, this method had been used to solve over 85 protein structures deposited in the PDB. The ABACUS protocol is available for download here.
We also employ x-ray crystallography, small angle X-ray scattering (SAXS) and chemical crosslinking as tools to characterize multidomain proteins and multiprotein complexes with hybrid computational strategies.
Nat Chem Biol. 2017 Jan 23;:
Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma.
Cancer Cell. 2017 Jan 09;31(1):50-63
Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1).
Medchemcomm. 2016 Sep 01;7(9):1793-1796
Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation.
J Leukoc Biol. 2016 Dec 29;:
Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.
Cancer Cell. 2016 Dec 12;30(6):891-908
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.
J Med Chem. 2016 Nov 2;
Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins.
J Biomol NMR. 2016 Oct 22;
Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1.
Discovery of a Potent, Selective and Cell-active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.
J Med Chem. 2016 Sep 1;
J Biomol Screen. 2016 Aug 31;
Senior Scientist, Princess Margaret Cancer Centre
Professor, Department of Medical Biophysics, Faculty of Medicine, University of Toronto
Chief Scientist, Structural Genomics Consortium, Toronto