SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis
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.
Authors
- Shingo Dan (ORCID: https://orcid.org/0000-0002-0022-2725)
- Sho Isoyama (ORCID: https://orcid.org/0000-0001-6751-1233)
- Shun‐Ichiro Kageyama (ORCID: https://orcid.org/0000-0002-6072-0144)
- Masami Nagahama (ORCID: https://orcid.org/0000-0001-6763-8058)
- Ukhyun Jo (ORCID: https://orcid.org/0000-0002-2826-1355)
- Keiichi Izumikawa (ORCID: https://orcid.org/0000-0001-7262-5403)
- Tomoko Morita (ORCID: https://orcid.org/0009-0004-9583-2471)
- Manabu Natsumeda (ORCID: https://orcid.org/0000-0003-3098-8323)
- Hiroyuki Sasanuma (ORCID: https://orcid.org/0000-0003-2824-4499)
- Yves Pommier (ORCID: https://orcid.org/0000-0002-3108-0758)
- Sota Tate (ORCID: https://orcid.org/0000-0001-7050-4560)
- Masayasu Okada (ORCID: https://orcid.org/0000-0002-9151-8184)
- Junya Kobayashi (ORCID: https://orcid.org/0000-0003-4645-7500)
- Shojiro Kitajima (ORCID: https://orcid.org/0000-0002-4000-0473)
- Daiki Taniyama (ORCID: https://orcid.org/0000-0001-5388-4581)
- Akihiro Ohashi (ORCID: https://orcid.org/0000-0002-4036-9385)
- Junko Murai (ORCID: https://orcid.org/0000-0003-2023-6160)
- Hiroshi Onji (ORCID: https://orcid.org/0000-0001-5778-0149)
- Mori Masaru
- Kohei Fujiwara
- Gaku Yamamoto
- Soichiro Tanaka
- Shigeki Higashiyama (ORCID: https://orcid.org/0000-0002-2417-3921)
- Soyoka Watanabe
- Hitoshi Saito (ORCID: https://orcid.org/0000-0002-7986-0913)
- Akane Ogawa
- Takayuki Ohga
Institutions
- Keio University (JP)
- Meiji Pharmaceutical University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Chiba Cancer Center (JP)
- National Cancer Institute (US)
- National Cancer Center Hospital East (JP)
- Center for Cancer Research (US)
- Japanese Foundation For Cancer Research (JP)
- Ehime University (JP)
- Niigata University (JP)
- International University of Health and Welfare (JP)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1016/j.molcel.2025.01.008
- Citations
- 19
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 19.86
Funders
- National Cancer Center Japan
- Keio University
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Fusion Oriented REsearch for disruptive Science and Technology