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 in biochemistry 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.

Research Areas

The huntingtin is a ~348 kDa proteinexpressed in every cell of our bodies and is often thought of as a "swiss army knife" protein, implicated in a plethora of cellular functions ranging from transcriptional regulation and DNA damage repair to axonal transport and proteostasis. The diversity of huntingtin functions is attributed to its ability to interact with thousands of proteins, with different huntingtin scaffolded complexes thought to execute its range of functions. However, the molecular details of how the huge huntingtin protein can interact its large diaspora of binding partners, how

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

Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40.
Alteen MG, Deme JC, Alvarez CP, Loppnau P, Hutchinson A, Seitova A, Chandrasekaran R, Silva Ramos E, Secker C, Alqazzaz M, Wanker EE, Lea SM, Arrowsmith CH, Harding RJ
Structure. 2023 . doi: 10.1016/j.str.2023.06.002
PMID: 37390814

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.. 2019 . doi: 10.1074/jbc.RA118.007204
PMID: 30842263

2024

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.
Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M
ACS Omega. 09.01.2024 9(1):917-924. doi: 10.1021/acsomega.3c07070
PMID: 38222562

2023

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.
Gall-Duncan T, Luo J, Jurkovic CM, Fischer LA, Fujita K, Deshmukh AL, Harding RJ, Tran S, Mehkary M, Li V, Leib DE, Chen R, Tanaka H, Mason AG, Lévesque D, Khan M, Razzaghi M, Prasolava T, Lanni S, Sato N, Caron MC, Panigrahi GB, Wang P, Lau R, Castel AL, Masson JY, Tippett L, Turner C, Spies M, La Spada AR, Campos EI, Curtis MA, Boisvert FM, Faull RLM, Davidson BL, Nakamori M, Okazawa H, Wold MS, Pearson CE
Cell. 05.10.2023 . doi: 10.1016/j.cell.2023.09.008
PMID: 37827155

Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6.
Harding RJ, Franzoni I, Mann MK, Szewczyk MM, Mirabi B, Ferreira de Freitas R, Owens DDG, Ackloo S, Scheremetjew A, Juarez-Ornelas KA, Sanichar R, Baker RJ, Dank C, Brown PJ, Barsyte-Lovejoy D, Santhakumar V, Schapira M, Lautens M, Arrowsmith CH
J Med Chem. 27.07.2023 . doi: 10.1021/acs.jmedchem.3c00314
PMID: 37499118

The Canadian Open Neuroscience Platform-An open science framework for the neuroscience community.
Harding RJ, Bermudez P, Bernier A, Beauvais M, Bellec P, Hill S, Karakuzu A, Knoppers BM, Pavlidis P, Poline JB, Roskams J, Stikov N, Stone J, Strother S, Evans AC
PLoS Comput Biol. 27.07.2023 19(7):e1011230. doi: 10.1371/journal.pcbi.1011230
PMID: 37498959

Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40.
Alteen MG, Deme JC, Alvarez CP, Loppnau P, Hutchinson A, Seitova A, Chandrasekaran R, Silva Ramos E, Secker C, Alqazzaz M, Wanker EE, Lea SM, Arrowsmith CH, Harding RJ
Structure. 20.06.2023 . doi: 10.1016/j.str.2023.06.002
PMID: 37390814

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

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

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

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