染色体外 DNA 生物发生和基因组 DNA 修复的不同途径

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-01-13 DOI:10.1158/2159-8290.CD-23-1117

John C Rose, Julia A Belk, Ivy Tsz-Lo Wong, Jens Luebeck, Hudson T Horn, Bence Daniel, Matthew G Jones, Kathryn E Yost, King L Hung, Kevin S Kolahi, Ellis J Curtis, Calvin J Kuo, Vineet Bafna, Paul S Mischel, Howard Y Chang

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引用次数: 0

摘要

染色体外DNA（ecDNA）上的癌基因扩增是癌症中普遍存在的驱动事件，但我们对ecDNA如何形成的了解却很有限。在这里，我们将基于CRISPR的ecDNA诱导方法与新形成的ecDNA的广泛表征结合起来，研究它们的生物发生过程。我们发现，无论三维基因组背景如何，DNA环化都是高效的，800kb、1 Mb 和 1.8 Mb ecDNA 的形成率都达到或超过了 15%。我们发现非同源末端连接和微同源介导的末端连接都有助于ecDNA的形成，而抑制DNA-PKcs和ATM对ecDNA的形成具有相反的影响。EcDNA和相应的染色体切除疤痕的形成速度明显不同，对DNA-PKcs和ATM抑制的反应也不同。综上所述，我们的研究结果支持蜕变DNA形成模型，在该模型中，双链断裂末端与其合法连接伙伴解离，然后非法末端连接形成蜕变DNA和切除疤痕。

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Disparate Pathways for Extrachromosomal DNA Biogenesis and Genomic DNA Repair.

Significance: Our study harnesses a CRISPR-based method to examine ecDNA biogenesis, uncovering efficient circularization between double-strand breaks. ecDNAs and their corresponding chromosomal scars can form via nonhomologous end joining or microhomology-mediated end joining, but the ecDNA and scar formation processes are distinct. Based on our findings, we establish a mechanistic model of excisional ecDNA formation.

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.