Topoisomerase III-beta protects from immune dysregulation and tumorigenesis

作者：Md Rasel Al Mahmud, Simone Andrea Baechler, Anjali Dhall, Sourav Saha, Hongliang Zhang, Laura Bassel, Shuling Zhang, Min-Jung Lee, Nahoko Sato, Shraddha Rastogi, Suresh Kumar, Muhammad Shamsul Alam, Liton Kumar Saha, Beverly A. Mock, Valentina M. Factor, Yves G. Pommier · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ady7028 · 被引用次数：2 · 研究领域：Cancer therapeutics and mechanisms、Cytokine Signaling Pathways and Interactions、Blood disorders and treatments

Topoisomerase III-beta (Top3b) reduces nucleic acid torsional stress and intertwining generated during RNA and DNA metabolism while protecting the genome from pathological R-loops, which otherwise result in DNA breakage and genome instability. By studying Top3b knockout mice ( Top3b -KO), we find that the loss of Top3b accelerates the development of spontaneous atypical lymphoid hyperplasia and lymphomas arising in spleens and lymph nodes, organs with prominent Top3b expression. Aging Top3b -KO mice also display splenomegaly and systemic immune alterations including neutrophilia and lymphopenia consistent with chronic inflammation. At the molecular level, Top3b deficiency causes genome-wide R-loop accumulation in splenocytes as measured by CUT&Tag sequencing. Increased R-loops are associated with genomic breaks and activation of immune signaling pathways including innate and adaptive immune cell signaling, IL-4 signaling, FAK signaling, and cGAS-STING. In addition, knocking-out Top3b promotes the rapid development of syngeneic EL4 T cell lymphomas. In conclusion, our work implies that Top3b protects from lymphoma, tumorigenesis, and immune dysregulations.