Reference - Detail
| RRC ID | 85546 |
|---|---|
| Author | Ogawa A, Izumikawa K, Tate S, Isoyama S, Mori M, Fujiwara K, Watanabe S, Ohga T, Jo U, Taniyama D, Kitajima S, Tanaka S, Onji H, Kageyama SI, Yamamoto G, Saito H, Morita TY, Okada M, Natsumeda M, Nagahama M, Kobayashi J, Ohashi A, Sasanuma H, Higashiyama S, Dan S, Pommier Y, Murai J. |
| Title | SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis. |
| Journal | Mol Cell |
| 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. |
| Volume | 85(5) |
| Pages | 894-912.e10 |
| Published | 2025-3-6 |
| DOI | 10.1016/j.molcel.2025.01.008 |
| PII | S1097-2765(25)00042-5 |
| PMID | 39909041 |
| PMC | PMC11890970 |
| MeSH | Apoptosis* / drug effects Cell Line, Tumor DNA, Ribosomal / genetics DNA, Ribosomal / metabolism Humans Myeloid Cell Leukemia Sequence 1 Protein / genetics Myeloid Cell Leukemia Sequence 1 Protein / metabolism Neoplasms* / drug therapy Neoplasms* / genetics Neoplasms* / metabolism Neoplasms* / pathology Nuclear Proteins* / genetics Nuclear Proteins* / metabolism RNA Polymerase I / genetics RNA Polymerase I / metabolism RNA, Ribosomal / biosynthesis RNA, Ribosomal / genetics RNA, Ribosomal / metabolism Ribosomes* / genetics Ribosomes* / metabolism Tumor Suppressor Protein p53* / genetics Tumor Suppressor Protein p53* / metabolism |
| IF | 15.584 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Bluesky |
| Total number of mentions | 7 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | pPCIH-vector (RDB20967) pPCIP-flag-SLFN11 (E209A/E214A) (RDB20964) pPCIH-flag-SLFN11 (WT) (RDB20968) pPCIH-flag-SLFN11 (E669Q) (RDB20969) pPCIH-flag-SLFN11 (E209A/E214A) (RDB20970) pPCIH-flag-SLFN11 (K652E) (RDB20971) pPCIH-flag-SLFN11 (S753D) (RDB20972) |