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Topoisomerase IIIb protects from immune dysregulation and tumorigenesis

ABSTRACT: 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, the 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. Additionally, knocking-out Top3b promotes the rapid development of syngeneic EL4 T-cell lymphomas. In conclusion, our work suggests that Top3b protects from lymphoma, tumorigenesis and immune dysregulations.

ORGANISM(S): Mus musculus

PROVIDER: GSE293641 | GEO | 2025/09/05

REPOSITORIES: GEO

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Topoisomerase IIIb protects from immune dysregulation and tumorigenesis

Project description: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, the 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. Additionally, knocking-out Top3b promotes the rapid development of syngeneic EL4 T-cell lymphomas. In conclusion, our work suggests that Top3b protects from lymphoma, tumorigenesis and immune dysregulations.

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Genome-wide homeostatic regulation of R-loops by the dual RNA-DNA topoisomerase, topoisomerase III-β (TOP3B) III

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