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.
DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models.
Nat Commun. 2018 May 15;9(1):1915
Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.
J Med Chem. 2018 May 09;:
Oncotarget. 2018 Apr 06;9(26):18480-18493
Elife. 2018 Apr 20;7:
Cell Rep. 2018 Apr 10;23(2):568-583
SLAS Discov. 2018 Mar 01;:2472555218766278
Revealing the Protein Propionylation Activity of the Histone Acetyltransferase Males absent on the first (MOF).
J Biol Chem. 2018 Jan 10;:
Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).
J Med Chem. 2017 Dec 15;:
Structural and Functional Survey of Environmental Aminoglycoside Acetyltransferases Reveals Functionality of Resistance Enzymes.
ACS Infect Dis. 2017 Sep 08;3(9):653-665
Nat Commun. 2017 Nov 15;8(1):1527
Senior Scientist, Princess Margaret Cancer Centre
Professor, Department of Medical Biophysics, Faculty of Medicine, University of Toronto
Chief Scientist, Structural Genomics Consortium, Toronto