Al Mahmud Md Rasel, Baechler Simone Andrea, Dhall Anjali, Saha Sourav, Zhang Hongliang, Zhang Shuling, Lee Min-Jung, Sato Nahoko, Rastogi Shraddha, Kumar Suresh, Alam Muhammad S, Saha Liton Kumar, Mock Beverly A, Factor Valentina M, Pommier Yves
Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
bioRxiv. 2025 Mar 15:2025.03.13.643061. doi: 10.1101/2025.03.13.643061.
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 lymphoid tumors arising in spleens and lymph nodes, the organs with prominent Top3b expression. Aging Top3b-KO mice also display splenomegaly and systemic immune alterations including neutrophilia and lymphopenia suggestive of 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 is associated with genomic DNA breaks and activation of immune signaling pathways including the IL-6 signaling, interleukin-7 signaling and cGAS-STING. Moreover, knocking-out Top3b promotes the rapid development of syngeneic EL4 T-cell lymphomas. In conclusion, our work implies that, in addition to its role in preserving the nervous system, Top3b protects from tumorigenesis and immune dysregulations.
拓扑异构酶III-β（Top3b）可降低RNA和DNA代谢过程中产生的核酸扭转应力和缠结，同时保护基因组免受病理性R环的影响，否则会导致DNA断裂和基因组不稳定。通过研究Top3b基因敲除小鼠（Top3b-KO），我们发现Top3b的缺失加速了脾脏和淋巴结中自发淋巴肿瘤的发展，而脾脏和淋巴结是Top3b表达显著的器官。衰老的Top3b-KO小鼠还表现出脾肿大和全身免疫改变，包括嗜中性粒细胞增多和淋巴细胞减少，提示存在慢性炎症。在分子水平上，通过CUT&Tag测序测量，Top3b缺乏导致脾细胞中全基因组R环积累。R环增加与基因组DNA断裂以及免疫信号通路的激活有关，包括IL-6信号通路、白细胞介素-7信号通路和cGAS-STING。此外，敲除Top3b可促进同基因EL4 T细胞淋巴瘤的快速发展。总之，我们的工作表明，除了在保护神经系统中的作用外，Top3b还能预防肿瘤发生和免疫失调。
