SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

doi:10.1016/j.molcel.2025.01.008

. 2025 Mar 6;85(5):894-912.e10.

doi: 10.1016/j.molcel.2025.01.008. Epub 2025 Feb 4.

SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

Akane Ogawa¹, Keiichi Izumikawa², Sota Tate³, Sho Isoyama⁴, Masaru Mori¹, Kohei Fujiwara⁵, Soyoka Watanabe¹, Takayuki Ohga², Ukhyun Jo⁶, Daiki Taniyama⁶, Shojiro Kitajima¹, Soichiro Tanaka¹, Hiroshi Onji⁵, Shun-Ichiro Kageyama⁷, Gaku Yamamoto⁸, Hitoshi Saito⁸, Tomoko Yamamori Morita⁸, Masayasu Okada⁹, Manabu Natsumeda¹⁰, Masami Nagahama², Junya Kobayashi¹¹, Akihiro Ohashi⁸, Hiroyuki Sasanuma¹², Shigeki Higashiyama¹³, Shingo Dan⁴, Yves Pommier¹⁴, Junko Murai¹⁵

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
PMCID: PMC11890970 (available on 2026-03-06)
DOI: 10.1016/j.molcel.2025.01.008

SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

Akane Ogawa et al. Mol Cell. 2025.

. 2025 Mar 6;85(5):894-912.e10.

doi: 10.1016/j.molcel.2025.01.008. Epub 2025 Feb 4.

Authors

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
PMCID: PMC11890970 (available on 2026-03-06)
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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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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References

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1. Lafontaine DLJ, Riback JA, Bascetin R, and Brangwynne CP (2021). The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol 22, 165–182. 10.1038/s41580-020-0272-6. - DOI - PubMed
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[1] Pelletier J, Thomas G, and Volarevic S (2018). Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer 18, 51–63. 10.1038/nrc.2017.104. - DOI - PubMed

[2] Pelletier J, Thomas G, and Volarevic S (2018). Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer 18, 51–63. 10.1038/nrc.2017.104. - DOI - PubMed

[3] Lafontaine DLJ, Riback JA, Bascetin R, and Brangwynne CP (2021). The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol 22, 165–182. 10.1038/s41580-020-0272-6. - DOI - PubMed

[4] Lafontaine DLJ, Riback JA, Bascetin R, and Brangwynne CP (2021). The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol 22, 165–182. 10.1038/s41580-020-0272-6. - DOI - PubMed

[5] Schmickel RD (1973). Quantitation of human ribosomal DNA: hybridization of human DNA with ribosomal RNA for quantitation and fractionation. Pediatr Res 7, 5–12. 10.1203/00006450-197301000-00002. - DOI - PubMed

[6] Schmickel RD (1973). Quantitation of human ribosomal DNA: hybridization of human DNA with ribosomal RNA for quantitation and fractionation. Pediatr Res 7, 5–12. 10.1203/00006450-197301000-00002. - DOI - PubMed

[7] Stults DM, Killen MW, Pierce HH, and Pierce AJ (2008). Genomic architecture and inheritance of human ribosomal RNA gene clusters. Genome Res 18, 13–18. 10.1101/gr.6858507. - DOI - PMC - PubMed

[8] Stults DM, Killen MW, Pierce HH, and Pierce AJ (2008). Genomic architecture and inheritance of human ribosomal RNA gene clusters. Genome Res 18, 13–18. 10.1101/gr.6858507. - DOI - PMC - PubMed

[9] Nemeth A, and Grummt I (2018). Dynamic regulation of nucleolar architecture. Curr Opin Cell Biol 52, 105–111. 10.1016/j.ceb.2018.02.013. - DOI - PubMed

[10] Nemeth A, and Grummt I (2018). Dynamic regulation of nucleolar architecture. Curr Opin Cell Biol 52, 105–111. 10.1016/j.ceb.2018.02.013. - DOI - PubMed

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SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

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SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

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