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

作者：Roderic Espín, Ferran Medina‐Jover, Javier Sigüenza-Andrade, Sònia Farran-Matas, Francesca Mateo, Agnes Figueras, Rosario T. Sanz, Guillermo P. Vicent, Arzoo Shabbir, Lara Ruiz-Auladell, Emilio Racionero-Andrés, Irene García, Alexandra Baiges, Lídia Franco-Luzón, Adrián Martínez-Tébar, Miguel Angel Pardo-Cea, María Martínez‐Iniesta, X. Wang, Elisabet Cuyàs, Javier A. Menéndez, Marta Lopez-Cerda, Purificacı́on Muñoz, Ivonne Richaud, Ángel Raya, Isabel Fabregat, Alberto Villanueva, Xènia Serrat, Julián Cerón, Montserrat Alemany, Inés Guix, Andrea Herencia-Ropero, Violeta Serra, Rehna Krishnan, Karim Mekhail, Razqallah Hakem, Jordi Bruna, Mary Helen Barcellos‐Hoff, Francesc Viñals, Àlvaro Aytés, Miguel Ángel Pujana · 发表于：NAR Cancer · 年份：2025 · DOI：10.1093/narcan/zcaf007 · 被引用次数：3 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Cancer Genomics and Diagnostics

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 PARP1 and POLQ expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with HIF1A mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or HIF1A 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.