Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment

Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood. Here, we show that alt-EJ is suppressed by hypoxia while positively associated with MYC (myelocytomatosis oncogene) transcriptional activity. Hypoxia reduces <i>PARP1</i> and <i>POLQ</i> expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with <i>HIF1A</i> mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or <i>HIF1A</i> expression depletion, combined with PARP or POLθ inhibition, synergistically reduces the colony-forming capacity of cancer cells. Deep learning reveals the anticorrelation between alt-EJ and hypoxia across regions in tumor images, and the predictions for these and MYC activity achieve area under the curve values between 0.70 and 0.86. These findings further highlight the critical role of hypoxia in modulating DNA repair and present a strategy for predicting and improving outcomes centered on targeting alt-EJ.

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Publication Details

Journal
NAR Cancer
Published
2025-01-15
DOI
https://doi.org/10.1093/narcan/zcaf007
Citations
3
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
3.14

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Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment

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NAR Cancer
PARP inhibition in cancer therapy
3.14
article

Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment

X. Wang, Alberto Villanueva, Xènia Serrat, Àlvaro Aytés, Purificacı́on Muñoz, Miguel Ángel Pujana, Guillermo P. Vicent, Irene García, Montserrat Alemany, Julián Cerón, Inés Guix, Francesc Viñals, Marta Lopez-Cerda, Sònia Farran-Matas, Alexandra Baiges, Elisabet Cuyàs, Mary Helen Barcellos‐Hoff, Albert Figueras, Roderic Espín, Ferran Medina‐Jover, Razqallah Hakem, Lídia Franco-Luzón, Francesca Mateo, Jordi Bruna, Rehna Krishnan, Violeta Serra, Adrián Martínez-Tébar, Javier A. Menéndez, Karim Mekhail, Isabel Fabregat, Rosario T. Sanz, Andrea Herencia-Ropero, Ángel Raya, María Martínez‐Iniesta, Arzoo Shabbir, Lara Ruiz-Auladell, Emilio Racionero-Andrés, Ivonne Richaud, Javier Sigüenza-Andrade
article en
3 citations

Abstract

Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood. Here, we show that alt-EJ is suppressed by hypoxia while positively associated with MYC (myelocytomatosis oncogene) transcriptional activity. Hypoxia reduces <i>PARP1</i> and <i>POLQ</i> expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with <i>HIF1A</i> mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or <i>HIF1A</i> expression depletion, combined with PARP or POLθ inhibition, synergistically reduces the colony-forming capacity of cancer cells. Deep learning reveals the anticorrelation between alt-EJ and hypoxia across regions in tumor images, and the predictions for these and MYC activity achieve area under the curve values between 0.70 and 0.86. These findings further highlight the critical role of hypoxia in modulating DNA repair and present a strategy for predicting and improving outcomes centered on targeting alt-EJ.

NAR CancerVol. 7(1)
Institució Catalana de Recerca i Estudis Avançats (ES), Universitat Autònoma de Barcelona (ES), University Health Network (CA), Consejo Superior de Investigaciones Científicas (ES), University of California, San Francisco (US), University of Toronto (CA), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), Princess Margaret Cancer Centre (CA), Institut d'Investigació Biomédica de Bellvitge (ES), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), Institut Català d'Oncologia (ES), Institut d'Investigació Biomèdica de Girona (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Medical Research Network (US), Institut de Biologia Molecular de Barcelona (ES), UCSF Helen Diller Family Comprehensive Cancer Center (US), Universitat de Barcelona (ES)
U.S. Department of Defense, Albert Einstein Cancer Center, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, Generalitat de Catalunya, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Departament de Salut, Generalitat de Catalunya, Agencia Estatal de Investigación, DOD Prostate Cancer Research Program
Good health and well-being
Openalex Percentile: Top 9%
PARP inhibition in cancer therapy
3.14
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