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  3. DDX3X mutation and Epstein-Barr virus cooperate to induce R-loop-dependent oncogenesis

DDX3X mutation and Epstein-Barr virus cooperate to induce R-loop-dependent oncogenesis

  • Cell Rep. 2025 Sep 23;44(9):116237. doi: 10.1016/j.celrep.2025.116237.
Hua-Man Cai 1,  Yu-Ran Qiu 1,  Yun Tan 1,  Kun Cai 1,  Shu Cheng 1,  Hui-Juan Zhong 1,  Di Fu 1,  Hai-Yang Lu 1,  Guo-Yu Meng 1,  Yan Zhao 1,  Zheng Ruan 1,  Wen-Fang Wang 2,  Min Lu 1,  Jian Zhang 3,  Zhu Chen 4,  Sai-Juan Chen 4,  Jie Xiong 5,  Wei-Li Zhao 6
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
  • 4 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
  • 5 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xiongjie_sih@163.com.
  • 6 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China. Electronic address: zhao.weili@yahoo.com.
PMID: 40913762 DOI: 10.1016/j.celrep.2025.116237
Abstract

RNA helicase DDX3X is generally implicated in inflammasome activation and anti-viral responses. We characterize the common features of scattered DDX3X mutations in lymphoid cancers using molecular dynamics simulation and crystallization, thereby demonstrating their crucial role in Epstein-Barr virus (EBV) lytic gene-driven oncogenic processes. The DDX3X mutation is significantly related to impaired stimulator of interferon genes (STING)/ interferon regulatory factor 7 (IRF-7)/interferon (IFN)-α/β-mediated innate immunity, overexpression of EBV lytic gene BNLF2b, and increased formation of R-loops. In Ddx3x449_450ET>DP conditional knockin transgenic mice, BNLF2b expression induces R-loop accumulation, genomic instability, and abnormal proliferation of CD3-/CD19-/NK1.1+ cells, thereby promoting malignant progression. The DNA-damaging agent etoposide enhances gamma-H2A histone family member X (γ-H2AX) co-localizing with R-loops, heightens genomic instability beyond cellular tolerance, and eventually triggers synthetic lethality in DDX3XmutBNLF2b+ tumors. These findings provide a better understanding of the functional interaction of the DDX3X mutation with EBV to provoke R-loop-dependent oncogenesis, shedding light on the pathogenic mechanism of EBV and future therapeutic approaches targeting R-loops in diseases involving RNA helicase alterations.

Keywords

CP: Cancer; CP: Genomics; DDX3X; DNA damage; Epstein-Barr virus; R-loops; genomic instability; oncogenesis; synthetic lethality.

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