SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

  • Mol Cell. 2025 Jan 30:S1097-2765(25)00042-5. doi: 10.1016/j.molcel.2025.01.008.
Akane Ogawa  1 ,  Keiichi Izumikawa  2 ,  Sota Tate  3 ,  Sho Isoyama  4 ,  Masaru Mori  1 ,  Kohei Fujiwara  5 ,  Soyoka Watanabe  1 ,  Takayuki Ohga  2 ,  Ukhyun Jo  6 ,  Daiki Taniyama  6 ,  Shojiro Kitajima  1 ,  Soichiro Tanaka  1 ,  Hiroshi Onji  5 ,  Shun-Ichiro Kageyama  7 ,  Gaku Yamamoto  8 ,  Hitoshi Saito  8 ,  Tomoko Yamamori Morita  8 ,  Masayasu Okada  9 ,  Manabu Natsumeda  10 ,  Masami Nagahama  2 ,  Junya Kobayashi  11 ,  Akihiro Ohashi  8 ,  Hiroyuki Sasanuma  12 ,  Shigeki Higashiyama  13 ,  Shingo Dan  4 ,  Yves Pommier  14 ,  Junko Murai  15
Affiliations
  • 1. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan.
  • 2. Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Tokyo 204-8588, Japan.
  • 3. Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
  • 4. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
  • 5. Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
  • 6. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20814, USA.
  • 7. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Chiba 277-8577, Japan.
  • 8. Division of Collaborative Research and Development, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan.
  • 9. Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Brain Tumor Biology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
  • 10. Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Advanced Treatment of Neurological Diseases Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
  • 11. Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan; Department of Radiological Sciences, School of Health Sciences at Narita, International University of Health and Welfare, Narita, Tokyo 286-0048, Japan.
  • 12. Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-0057, Japan.
  • 13. Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Department of Oncogenesis and Tumor Regulation, Osaka International Cancer Institute, Osaka 103-0027, Japan.
  • 14. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20814, USA. Electronic address: [email protected].
  • 15. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan; Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Toon, Ehime 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan; Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan. Electronic address: [email protected].
PMID: 39909041 DOI: 10.1016/j.molcel.2025.01.008
Abstract

Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent Apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to Apoptosis in response to replication stress. SLFN11's Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and Other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human Cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes Cancer cells to chemotherapeutic agents.

Keywords
DNA damage; TP53; apoptosis; cell cycle checkpoint; chromatin; rRNA; replication stress; ribosome biogenesis; stress response; topoisomerase inhibitor.
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