Les dommages à l'ADN peuvent causer l’inactivation ou l’activation aberrante de divers gènes, ce qui conduit au développement du cancer. Les mécanismes de réparation de l'ADN permettent aux cellules normales de survivre à ces lésions, mais peuvent aussi compromettre l'efficacité des traitements de chimiothérapie qui tuent les cellules cancéreuses en induisant des dommages massifs à l'ADN. La recherche sur la réparation de l’ADN est donc cruciale pour mieux comprendre les mécanismes menant au développement du cancer, et pour permettre la mise au point de nouvelles modalités de traitements.

Nous utilisons des cellules humaines en culture et la levure Saccharomyces cerevisiae comme modèles expérimentaux, ainsi que des approches de microscopie par fluorescence, de biochimie et de génétique, pour mieux comprendre comment les cellules cancéreuses répondent aux médicaments anti-cancer qui causent des dommages à l’ADN. Plus particulièrement, nous nous intéressons aux mécanismes qui influencent l’efficacité des agents de chimiothérapie qui agissent en prévenant la duplication du matériel génétique (réplication de l’ADN).

Une meilleure compréhension de ces phénomènes conduira à la mise au point de nouvelles stratégies de traitement contre le cancer, et identifiera des marqueurs moléculaires permettant de mieux catégoriser les tumeurs afin de définir les traitements appropriés pour chaque patient.

Hugo Wurtele, Ph.D. dirige l'unité de recherche Réplication de l'ADN et stabilité du génome. Il est professeur titulaire au Département de médecine de l'Université de Montréal. 

Mehrjoo, Y.; Campeau, P. M.; Al Abdi, L.; Aldowaish, A.; Abouyousef, O.; Alkuraya, F. S.; Codina-Solà, M.; Cueto-González, A. M.; Wurtele, H. (2024) Functional studies in yeast confirm the pathogenicity of a new GINS3 Meier-Gorlin syndrome variant. Clin Genet. doi: 10.1111/cge.14545

Bottardi S, Layne T, Ramon AdlC, Quansah N, Wurtele H, Affar EB, Milot E (2024) MNDA, a PYHIN factor involved in transcriptional regulation and apoptosis control in leukocytes. Front Immunol. 15:1395035

Yates M, Marois I, St-Hilaire E, Ronato D, Djerir B, Brochu C, Morin T, Hammond-Martel I, Gezzar-Dandashi S, Casimir L, Drobetsky E, Cappadocia L, Masson J, Wurtele H, Maréchal A (2024) SMARCAL1 ubiquitylation controls its association with RPA-ssDNA and promotes fork stability. PLoS Biology 22(3)

Tremblay R, Mehrjoo Y, Ahmed O, Simoneau A, McQuaid ME, Affar EB, Nislow C, Giaever G, Wurtele H. (2023) Persistent acetylation of newly synthesized histones inhibits DNA replication origin activity. Mol Cell Biol 9:1-30. doi: 10.1080/10985549.2023.2259739

Homsi C, Rajan R, Minati R, St-Hilaire E; Bonneil E, Dufresne S, Wurtele H, Verreault A, Thibault P. (2023) A rapid and efficient method for the extraction of histone proteins. Journal of Proteome Research, doi: 10.1021/acs.jproteome.3c00266

Bélanger F, Roussel C, Sawchyn C, Gezzar-Dandashi S, Mallette FA, Wurtele H*, Drobetsky EA* (2023) Control of UV damage repair during S phase via Dyrk1A-dependent regulation of cyclin D1/p21waf1cip1 stability. Journal of Biological Chemistry 8: 104900, doi: 10.1016/j.jbc.2023.104900

Lemay J-F, St-Hilaire E, Gezzar-Dandashi S, McQuaid M, Ronato DA, Gao Y, Bélanger F, Sawchyn C, Kimenyi Ishimwe AB, Mallette FA, Masson J-Y, Drobetsky EA, Wurtele H (2022) A genome-wide screen identifies SCAI as a modulator of the UV-induced replicative stress response in human cells. PLoS Biol. 2022 Oct 10;20(10)
. doi: 10.1371/journal.pbio.3001543

McQuaid ME, Ahmed K, Tran S, Rousseau J, Shaheen R, Kernohan K, Yuki K, Grover P, Dreseris E, Ahmed S, Dupuis L, Stimec J, Shago M, Alhassnan Z, Tremblay R, Maass PS, Wilson M, Grunebaum E, Boycott K, Boisvert FM, Maddirevula S, Faqeih E, Almanjomi F, Khan Z, Alkuraya F, Campeau P, Kannu P, Campos E, Wurtele H (2022) Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin Syndrome. JCI Insight 7(10)

Batenburg N, Mersaoui S, Walker JR, Coulombe Y, Hammond-Martel I, Wurtele H, Masson J-Y, Zhu XD (2021) Cockayne syndrome group B protein regulates fork restart, fork progression, and MRE11-dependent fork degradation in BRCA1/2-deficient cells. Nucleic Acids Research, doi: 10.1093/nar/gkab1173

Uriarte M, Sen Nkwe N, Tremblay R, Mashtalir N, Barbour H, Abdelhadi D, Darracq A, Desjardins-Lecavalier N, Sapieha P, Masson JY, Sergeev M, Milot E, Wurtele H and Affar EB. (2021) Liquid phase separation of the mammalian proteasome links amino acid supply to apoptosis. Nature Communications, 12(1):6984. doi: 10.1038/s41467-021-27306-4

Nabais Sá MJ, Miller KA, McQuaid M, Koelling N, Wilkie AOM, Wurtele H, de Brouwer APM, Oliveira J. (2021) A biallelic GINS2 variant, p.(Arg114Leu), causes Meier-Gorlin syndrome with craniosynostosis. Journal of Medical Genetics, doi: 10.1136/jmedgenet-2020-107572

Hammond-Martel I, Verreault A, Wurtele H. (2021) Chromatin dynamics and DNA replication roadblocks. DNA repair 104: 103140 https://doi.org/10.1016/j.dnarep.2021.103140

Abusarah J, Cui Y, EL-Hachem N, El-Kadiry AE, Hammond-Martel I, Wurtele H, Beaudry A, Raynal N J-M, Robert F, Pelletier J, Jankovic M, Mercier F, Kamyabiazar S, Annabi B, Rafei M. (2021) TACIMA-218: a novel pro-oxydant agent exhibiting selective anti-tumoral activity. Molecular Cancer Therapeutics 20(1):37-49

Benslimane Y, Bertomeu T*, Coulombe-Huntington J*, McQuaid M*, Papadopoli D, Avizonis D, De Sa Tarvares Russo M, Huard C, Topisirovic I, Wurtele H, Tyers M, Harrington L. (2020) Genome-wide screens reveal that resveratrol induces replicative stress in human cells. Molecular Cell 79(5):846-856 *: these authors contributed equally

El Hakim El Kadiry A, AbuSarah J, Cui YE, El-Hachem N, Hammond-Martel I, Wurtele H, Thomas S, Ahmadi M, Talbot A, Rafei M. (2020) A novel sulfonyl-based small molecule exhibiting anti-cancer properties. Frontiers in Pharmacology 11:237 doi.org/10.3389/fphar.2020.00237

Sen Nkwe N, Daou S, Uriarte M, Gagnon J, Iannantuono NV, Barbour H, Yu H, Masclef L, Fernandez E, Zamorano Cuervo N, Mashtalir N, Binan L, Sergeev M, Belanger F, Drobetsky E, Milot E, Wurtele H, Costantino S, and Affar EB. (2020) A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase. Journal of Cell Science, 133(4)
DOI: 10.1242/jcs.239236

Binan L, Bélanger F, Uriarte M, Lemay JF, Pelletier De Koninck JC, Roy J, Affar EB, Drobetsky E, Wurtele H, Costantino S. (2019) Opto-magnetic capture of individual cells based on visual phenotypes. Elife. doi: 10.7554/eLife.45239

Fortier E, Drobetsky E, Wurtele H. (2019) Know your limits: RPA availability and chemoresistance in ovarian cancer. Oncotarget. 10(8):800-802

Ghesquière P, Elsherbiny A, Fortier É, McQuaid M, Mazzaferri J, Bélanger F, Cheriet F, Drobetsky E, Wurtele H, Costantino S (2019) An open-source algorithm for rapid unbiased determination of DNA fiber length, DNA repair, 74:26-37

Bélanger F, Fortier E, Dubé M, Lemay JF, Buisson R, Masson JY, Elsherbiny A, Costantino S, Carmona E, Mes-Masson AM, Wurtele H*, Drobetsky E* (2018) Replication Protein A Availability During DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells. Cancer Research, 78(19):5561-557. * : co-corresponding authors

Simoneau A, Ricard É, Wurtele H (2018) An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres. PLoS Genetics. 14(4)

Chaillot J, Tebbji F, Garcia C, Wurtele H, Pelletier R, Sellam A. (2017) pH-dependant antifungal activity of valproic acid against the human fungal pathogen Candida albicans. Frontiers in Microbiology. 8: 1956

Modica G, Skorobogata O, Sauvageau E, Vissa A, Yip CM, Kim PK, Wurtele H, Lefrancois S. (2017) Rab7 palmitoylation is required for efficient endosome-to-TGN trafficking. J Cell Sci. 130(15):2579-2590

Guillemette B, Hammond-Martel I, Wurtele H, Verreault A. (2016) Production and Purification of Antibodies Against Histone Modifications. Methods Mol Biol. 1528:149-164

Desfossés-Baron K, Hammond-Martel I, Simoneau A, Sellam A, Roberts S, Wurtele H. (2016) Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae. Scientific Reports. doi: 10.1038/srep36013

Simoneau A, Ricard É, Weber S, Hammond-Martel I, Wong LH, Sellam A, Giaever G, Nislow C, Raymond M, Wurtele H. (2016) Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signalling upon replicative stress. Nucleic Acids Research. 44(6):2706-26. PMID: 26748095

Bélanger F, Angers JP, Fortier É, Hammond-Martel I, Costantino S, Drobetsky E, Wurtele H. (2016) Mutations in Replicative Stress Response Pathways Are Associated with S Phase-Specific Defects in Nucleotide Excision Repair. Journal of Biological Chemistry 291(2):522-37. doi: 10.1074/jbc.M115.685883. PMID: 26578521

Daou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Ianantuono NVG, Nkwe NS, Motorina A, Pak H, Yu H, Wurtele H, Milot E, Mallette FA, Carbone M, Affar EB. (2015) The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and is Disrupted in Cancer. Journal of Biological Chemistry 290(48):28643-63. doi: 10.1074/jbc.M115.661553. PMID: 26416890

Gagnon J, Daou S, Zamorano N, Iannantuono NV, Hammond-Martel I, Mashtalir N, Bonneil E, Wurtele H, Thibault P, Affar el B. (2015) Undetectable Histone O-GlcNAcylation in Mammalian Cells. Epigenetics 10: 677-691

Simoneau A, Delgoshaie N, Celic I, Dai J, Costantino S, Boeke JD, Verreault A and Wurtele H (2015) Interplay between histone H3 lysine 56 deacetylation and chromatin modifiers in the response to replicative DNA damage. Genetics 200: 185-205

Wurtele H, Kaiser GS, Bacal J, St-Hilaire E, Lee EH, Tsao S, Dorn J, Maddox P, Lisby M, Pasero P, Verreault A. (2012) Histone H3 lysine 56 acetylation and the response to DNA replication fork damage. Molecular and Cellular Biology 32: 154-172

Tang Y, Holbert MA, Delgoshaie N, Wurtele H, Guillemette B*, Meeth K, Yuan H, Drogaris P, Lee EH, Durette C, Thibault P, Verreault A, Cole PA, Marmorstein R (2011) Structure of the Rtt109-AcCoA/Vps75 Complex and Implications for Chaperone-Mediated Histone Acetylation. Structure 19:221-31

Wurtele H, Tsao S, Lepine G, Mullick A, Tremblay J, Drogaris P, Lee E-H, Thibault P, Verreault A, Raymond M. (2010) Modulation of Histone H3 Lysine 56 Acetylation as an Antifungal Therapeutic Strategy. Nature Medicine 16: 774-780

Delgoshaie N, Wurtele H, Verreault A (2009) Histone acetylation floods the human cell cycle and DNA damage response. Cell Cycle 8: 1820

Wurtele H, Li, Q, Zhou H, Zhang Z, Verreault A (2009) [Histone acetylation and chromatin assembly]. Med Sci (Paris) 25: 121-122

Tang Y, Holbert MA, Wurtele H, Meeth K, Rocha W, Gharib M, Jiang E, Thibault P, Verrault A, Cole PA, Marmorstein R (2008) Fungal Rtt109 Histone Acetyltransferase: an Unexpected Structural Homolog of Metazoan p300/CBP. Nature Structural and Molecular Biology 15: 998

Drogaris P, Wurtele H, Masumoto H, Verreault A, Thibault P (2008) Comprehensive profiling of histone modifications and its applications in determining structure-function relationships. Analytical Chemistry 80: 6698-6707

Li Q, Zhou H, Wurtele H, Verreault A, Zhang Z, (2008) Acetylation of Lysine 56 on H3 Regulates CAF-1 Dependent Nucleosome Assembly. Cell 134: 244-255

Wurtele H, Verreault A. (2006) Histone post-translational modifications and the response to DNA double-strand breaks. Curr Opin Cell Biol 18: 137-144

Wurtele H, Chartrand P. (2006) Genome-wide scanning of HoxB1-associated loci in mouse ES cells using an open-ended Chromosome Conformation Capture methodology. Chromosome Research 14: 477-495

Wurtele H, Gusew N, Lussier R, Chartrand P. (2005) Characterization of in vivo recombination activities in the mouse embryo. Molecular Genetics and Genomics 273: 252-263

Wurtele H, Little KC, Chartrand P. (2003) Illegitimate DNA integration in mammalian cells. Gene Therapy 10: 1791-1799