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Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells

Author

Listed:
  • Ting Zhang

    (Max-Planck-Institute for Heart and Lung Research)

  • Carsten Künne

    (Max-Planck-Institute for Heart and Lung Research
    Max Planck Institute for Heart and Lung Research)

  • Dong Ding

    (Max-Planck-Institute for Heart and Lung Research)

  • Stefan Günther

    (Max-Planck-Institute for Heart and Lung Research
    Max Planck Institute for Heart and Lung Research)

  • Xinyue Guo

    (Max-Planck-Institute for Heart and Lung Research)

  • Yonggang Zhou

    (Max-Planck-Institute for Heart and Lung Research)

  • Xuejun Yuan

    (Max-Planck-Institute for Heart and Lung Research)

  • Thomas Braun

    (Max-Planck-Institute for Heart and Lung Research
    German Center for Cardiovascular Research (DZHK)
    German Center for Lung Research (DZL))

Abstract

Transcription replication collisions (TRCs) constitute a major intrinsic source of genome instability but conclusive evidence for a causal role of TRCs in tumor initiation is missing. We discover that lack of the H4K20-dimethyltransferase KMT5B (also known as SUV4-20H1) in muscle stem cells de-represses S-phase transcription by increasing H4K20me1 levels, which induces TRCs and aberrant R-loops in oncogenic genes. The resulting replication stress and aberrant mitosis activate ATR-RPA32-P53 signaling, promoting cellular senescence, which turns into rapid rhabdomyosarcoma formation when p53 is absent. Inhibition of S-phase transcription ameliorates TRCs and formation of R-loops in Kmt5b-deficient MuSCs, validating the crucial role of H4K20me1-dependent, tightly controlled S-phase transcription for preventing collision errors. Low KMT5B expression is prevalent in human sarcomas and associated with tumor recurrence, suggesting a common function of KMT5B in sarcoma formation. The study uncovers decisive functions of KMT5B for maintaining genome stability by repressing S-phase transcription via control of H4K20me1 levels.

Suggested Citation

  • Ting Zhang & Carsten Künne & Dong Ding & Stefan Günther & Xinyue Guo & Yonggang Zhou & Xuejun Yuan & Thomas Braun, 2022. "Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34577-y
    DOI: 10.1038/s41467-022-34577-y
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    References listed on IDEAS

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