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

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

  • Mol Cell. 2025 Aug 21;85(16):3090-3107.e11. doi: 10.1016/j.molcel.2025.07.007.
Lu-Ning Qin 1,  Ting Wu 1,  Xue-Ting Zhen 1,  Yun-Long Zhao 1,  Jie-Shi Zhou 1,  Shan-Bin Cheng 1,  Kai-Wen Wang 1,  Shuai Qiao 1,  Ding-Zhi Huang 2,  Heng Zhang 3,  Tao Sun 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
  • 2 Tianjin Medical University Cancer Institute and Hospital, Tianjin 300202, China. Electronic address: huangdingzhi@tjmuch.com.
  • 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China. Electronic address: zhangheng@nankai.edu.cn.
  • 4 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China. Electronic address: tao.sun@nankai.edu.cn.
PMID: 40769147 DOI: 10.1016/j.molcel.2025.07.007
Abstract

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 the multi-layer perceptron model, a series of imaging strategies in human Cancer cells, and clinical chip verification, we demonstrate that ecDNA biogenesis depends on transcription factor Yin Yang 1 (YY1)-mediated DNA looping coupled with religation catalyzed 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-targeted strategies in Cancer therapy.

Keywords

DNA looping; Lig3; PARylation; YY1; ecDNA.

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