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

MPS-Authors
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Zhang,  Ting
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Kuenne,  Carsten
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons284386

Ding,  Dong
Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251626

Guo,  Xinyue
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224110

Zhou,  Yonggang
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224106

Yuan,  Xuejun
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224052

Braun,  Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Zhang, T., Kuenne, C., Ding, D., Guenther, S., Guo, X., Zhou, Y., et al. (2022). Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells. NATURE COMMUNICATIONS, 13(1): 6907. doi:10.1038/s41467-022-34577-y.


Cite as: https://hdl.handle.net/21.11116/0000-000B-F097-B
Abstract
Suppression of transcription in S-phase is crucial to prevent genome instability. Zhang et al demonstrate that increase of H4K20me1 due to loss of Kmt5b cause genome instability in muscle stem cells, resulting in stem cell senescence but rhabdomyosarcoma formation when p53 is inactivated.
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.