Extrachromosomal DNA biogenesis is dependent on DNA looping and religation by YY1-Lig3-PARylation complex

The link between extrachromosomal DNA (ecDNA) and tumors has been well established, and its role in cancer is of increasing interest. While ecDNA is thought to originate from genomic instability, the molecular mechanisms driving DNA end ligation during ecDNA formation and the regulatory factors controlling its selective gene packaging remain unresolved. Here, using machine learning, bioinformatics, cellular assays, and clinical validation, we demonstrate that ecDNA biogenesis depends on YY1-mediated DNA looping coupled with ligation executed by DNA ligase 3 (Lig3), a mechanism that extends existing models. Notably, PARylation-dependent acidic microenvironments mediated by the Lig3-YY1 complex play a critical role in the formation of Z-DNA, which potentially facilitates the fusion-religation process to drive ecDNA biogenesis. Furthermore, our findings establish PARP inhibitors as specific agents for ecDNA-targeting strategies in cancer therapy.

染色体外DNA（extrachromosomal DNA, ecDNA）与肿瘤的关联已被充分证实，其在癌症中的作用也日益受到学界关注。尽管普遍认为ecDNA起源于基因组不稳定性，但ecDNA形成过程中驱动DNA末端连接的分子机制，以及调控其选择性基因包装的相关因子仍未明确。本研究借助机器学习（machine learning）、生物信息学（bioinformatics）分析、细胞实验与临床验证手段，证实ecDNA的生物发生依赖于YY1介导的DNA环化，以及由DNA连接酶3（DNA ligase 3, Lig3）执行的连接过程，该机制拓展了现有模型。值得注意的是，由Lig3-YY1复合物介导的、依赖于聚ADP核糖基化修饰（PARylation）的酸性微环境，在Z型DNA（Z-DNA）的形成中发挥关键作用，这一过程或可促进融合-连接过程，进而推动ecDNA的生物发生。此外，本研究成果确立了PARP抑制剂可作为靶向ecDNA的癌症治疗特异性药物。