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

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2025-03-07 eCollection Date: 2025-03-01 DOI:10.1093/narcan/zcaf007
Roderic Espín, Ferran Medina-Jover, Javier Sigüenza-Andrade, Sònia Farran-Matas, Francesca Mateo, Agnes Figueras, Rosario T Sanz, Guillermo Pablo Vicent, Arzoo Shabbir, Lara Ruiz-Auladell, Emilio Racionero-Andrés, Irene García, Alexandra Baiges, Lídia Franco-Luzón, Adrián Martínez-Tebar, Miguel Angel Pardo-Cea, María Martínez-Iniesta, Xieng Chen Wang, Elisabet Cuyàs, Javier A Menendez, Marta Lopez-Cerda, Purificacion Muñoz, Ivonne Richaud, Angel 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, Álvaro Aytes, Miquel Angel Pujana
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引用次数: 0

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.

利用替代末端连接的转录调控来预测癌症治疗。
选择性末端连接(Alternative end-joining, alt-EJ)是一种容易出错的DNA修复途径,缺乏同源重组的癌细胞依赖于这种途径,通过抑制聚(adp -核糖)聚合酶(PARP),使癌细胞容易受到合成致死的影响。靶向alt-EJ效应DNA聚合酶θ (POLθ),与PARP抑制剂协同作用并能克服耐药性,具有重要的临床前和临床意义。然而,alt-EJ的转录调控及其与驱动癌症进展过程的相互作用仍然知之甚少。在这里,我们发现alt-EJ受到缺氧的抑制,同时与MYC(髓细胞瘤癌基因)转录活性呈正相关。缺氧降低了PARP1和POLQ的表达,降低了MYC在它们的启动子上的结合,降低了PARylation和alt- ej介导的癌细胞DNA修复。HIF1A突变的肿瘤过表达alt-EJ基因特征。抑制缺氧诱导因子1α或HIF1A表达缺失,结合PARP或POLθ抑制,协同降低癌细胞的集落形成能力。深度学习揭示了alt-EJ与肿瘤图像各区域缺氧之间的反相关关系,并且对这些和MYC活性的预测达到了曲线值在0.70到0.86之间的区域。这些发现进一步强调了缺氧在调节DNA修复中的关键作用,并提出了以靶向alt-EJ为中心预测和改善结果的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
6.90
自引率
0.00%
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0
审稿时长
13 weeks
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