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  3. SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

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

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: pommier@nih.gov.
  • 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: murai.junko.nk@ehime-u.ac.jp.
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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