Rachel Harding Rachel Harding
Rachel Harding

Principal Investigator

University of Toronto
rachel.harding@utoronto.ca

Dr. Harding is an Assistant Professor at the Department of Pharmacology and Toxicology and a Principal Investigator at the Structural Genomics Consortium. Dr. Harding completed her undergraduate and DPhil in structural biology at the University of Oxford, before moving to the University of Toronto for her postdoctoral training. The focus of Dr. Harding’s research is the huntingtin protein, mutated in people with Huntington’s disease. Huntington’s is a devastating, incurable, genetic, neurodegenerative disease caused by a CAG-tract expansion in the Huntingtin gene. Dr. Harding studies the structure-function of the huntingtin protein in both its wildtype and disease forms, with a view to better understand the mechanisms of disease, as well as trying to find new avenues of therapeutic intervention.

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.
Harding RJ, Deme JC, Hevler JF, Tamara S, Lemak A, Cantle JP, Szewczyk MM, Begeja N, Goss S, Zuo X, Loppnau P, Seitova A, Hutchinson A, Fan L, Truant R, Schapira M, Carroll JB, Heck AJR, Lea SM, Arrowsmith CH
Commun Biol. 2021 4(1):1374. doi: 10.1038/s42003-021-02895-4
PMID: 34880419

Structure-Activity Relationship of USP5 Inhibitors.
Mann MK, Zepeda-Velázquez CA, González-Álvarez H, Dong A, Kiyota T, Aman AM, Loppnau P, Li Y, Wilson B, Arrowsmith CH, Al-Awar R, Harding RJ, Schapira M
J Med Chem. 2021 . doi: 10.1021/acs.jmedchem.1c00889
PMID: 34648286

2023

Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei.
MacDonald KM, Nicholson-Puthenveedu S, Tageldein MM, Khasnis S, Arrowsmith CH, Harding SM
Nat Commun. 02.02.2023 14(1):556. doi: 10.1038/s41467-023-36195-8
PMID: 36732527

2021

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.
Harding RJ, Deme JC, Hevler JF, Tamara S, Lemak A, Cantle JP, Szewczyk MM, Begeja N, Goss S, Zuo X, Loppnau P, Seitova A, Hutchinson A, Fan L, Truant R, Schapira M, Carroll JB, Heck AJR, Lea SM, Arrowsmith CH
Commun Biol. 08.12.2021 4(1):1374. doi: 10.1038/s42003-021-02895-4
PMID: 34880419

Structure-Activity Relationship of USP5 Inhibitors.
Mann MK, Zepeda-Velázquez CA, González-Álvarez H, Dong A, Kiyota T, Aman AM, Loppnau P, Li Y, Wilson B, Arrowsmith CH, Al-Awar R, Harding RJ, Schapira M
J Med Chem. 14.10.2021 . doi: 10.1021/acs.jmedchem.1c00889
PMID: 34648286

2020

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.
Szewczyk MM, Ishikawa Y, Organ S, Sakai N, Li F, Halabelian L, Ackloo S, Couzens AL, Eram M, Dilworth D, Fukushi H, Harding R, Dela Seña CC, Sugo T, Hayashi K, McLeod D, Zepeda C, Aman A, Sánchez-Osuna M, Bonneil E, Takagi S, Al-Awar R, Tyers M, Richard S, Takizawa M, Gingras AC, Arrowsmith CH, Vedadi M, Brown PJ, Nara H, Barsyte-Lovejoy D
Nat Commun. 14.05.2020 11(1):2396. doi: 10.1038/s41467-020-16271-z
PMID: 32409666

2019

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain.
Mann MK, Franzoni I, de Freitas RF, Tempel W, Houliston S, Smith L, Vedadi M, Arrowsmith CH, Harding RJ, Schapira M
J. Med. Chem.. 30.10.2019 . doi: 10.1021/acs.jmedchem.9b00988
PMID: 31663737

Open laboratory notebooks: good for science, good for society, good for scientists.
Schapira M, Harding RJ
F1000Res. 27.08.2019 8:87. doi: 10.12688/f1000research.17710.1
PMID: 31448096

Target highlights in CASP13: experimental target structures through the eyes of their authors.
Lepore R, Kryshtafovych A, Alahuhta M, Arora Veraszto H, Bomble YJ, Bufton JC, Bullock AN, Caba C, Cao H, Davies OR, Desfosses A, Dunne M, Fidelis K, Goulding CW, Gurusaran M, Gutsche I, Harding CJ, Hartmann MD, Hayes CS, Joachimiak A, Leiman PG, Loppnau P, Lovering AL, Lunin VV, Michalska K, Mir-Sanchis I, Mitra A, Moult J, Phillips GN, Pinkas DM, Rice PA, Tong Y, Topf M, Walton JD, Schwede T
Proteins. 23.08.2019 . doi: 10.1002/prot.25805
PMID: 31442339

Design and characterization of mutant and wild-type huntingtin proteins produced from a toolkit of scalable eukaryotic expression systems.
Harding RJ, Loppnau P, Ackloo S, Lemak A, Hutchinson A, Hunt B, Holehouse AS, Ho JC, Fan L, Toledo-Sherman L, Seitova A, Arrowsmith CH
J. Biol. Chem.. 06.03.2019 . doi: 10.1074/jbc.RA118.007204
PMID: 30842263

Open notebook science can maximize impact for rare disease projects.
Harding RJ
PLoS Biol. 29.01.2019 17(1):e3000120. doi: 10.1371/journal.pbio.3000120
PMID: 30689629

2018

Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.
Ferreira de Freitas R, Harding RJ, Franzoni I, Ravichandran M, Mann MK, Ouyang H, Lautens M, Santhakumar V, Arrowsmith CH, Schapira M
J. Med. Chem.. 09.05.2018 . doi: 10.1021/acs.jmedchem.8b00258
PMID: 29741882

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities.
Harding RJ, Tong YF
Acta Pharmacol Sin. 06.04.2018 39(5):754-769. doi: 10.1038/aps.2018.11
PMID: 29620053

Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.
Zhang H, Zhou B, Qin S, Xu J, Harding R, Tempel W, Nayak V, Li Y, Loppnau P, Dou Y, Min J
Genes Dev.. 21.03.2018 . doi: 10.1101/gad.311639.118
PMID: 29563185

2017

Small molecule antagonists of the interaction between the histone deacetylase 6 zinc-finger domain and ubiquitin.
Harding RJ, Ferreira de Freitas R, Collins PM, Franzoni I, Ravichandran M, Ouyang H, Juarez-Ornelas KA, Lautens M, Schapira M, von Delft F, Santhakumar V, Arrowsmith CH
J. Med. Chem.. 11.10.2017 . doi: 10.1021/acs.jmedchem.7b00933
PMID: 29019676

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.
Baker DA, Stewart LB, Large JM, Bowyer PW, Ansell KH, Jiménez-Díaz MB, El Bakkouri M, Birchall K, Dechering KJ, Bouloc NS, Coombs PJ, Whalley D, Harding DJ, Smiljanic-Hurley E, Wheldon MC, Walker EM, Dessens JT, Lafuente MJ, Sanz LM, Gamo FJ, Ferrer SB, Hui R, Bousema T, Angulo-Barturén I, Merritt AT, Croft SL, Gutteridge WE, Kettleborough CA, Osborne SA
Nat Commun. 05.09.2017 8(1):430. doi: 10.1038/s41467-017-00572-x
PMID: 28874661

2016

The substrate binding domains of human SIAH E3 ubiquitin ligases are now crystal clear.
Zhang Q, Wang Z, Hou F, Harding R, Huang X, Dong A, Walker JR, Tong Y
Biochim. Biophys. Acta. 21.10.2016 . doi: 10.1016/j.bbagen.2016.10.019
PMID: 27776223

Structural Basis of the Recruitment of Ubiquitin-Specific Protease USP15 by Spliceosome Recycling Factor SART3.
Zhang Q, Harding R, Hou F, Dong A, Walker JR, Bteich J, Tong Y
J. Biol. Chem.. 02.06.2016 . doi: 10.1074/jbc.M116.740787
PMID: 27255711

glqxz9283 sfy39587stf02 mnesdcuix8
sfy39587stf03