SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

被引：0

作者：

Ogawa, Akane ^{[1
]}

Izumikawa, Keiichi ^{[2
]}

Tate, Sota ^{[3
,4
]}

Isoyama, Sho ^{[5
]}

Mori, Masaru ^{[1
]}

Fujiwara, Kohei ^{[4
]}

Watanabe, Soyoka ^{[1
]}

Ohga, Takayuki ^{[2
]}

Jo, Ukhyun ^{[6
,7
]}

Taniyama, Daiki ^{[6
,7
]}

Kitajima, Shojiro ^{[1
]}

Tanaka, Soichiro ^{[1
]}

Onji, Hiroshi ^{[4
]}

Kageyama, Shun-Ichiro ^{[8
]}

Yamamoto, Gaku ^{[9
]}

Saito, Hitoshi ^{[9
]}

Morita, Tomoko Yamamori ^{[9
]}

Okada, Masayasu ^{[10
,11
]}

Natsumeda, Manabu ^{[12
]}

Nagahama, Masami ^{[2
]}

Kobayashi, Junya ^{[13
,14
]}

Ohashi, Akihiro ^{[9
]}

Sasanuma, Hiroyuki ^{[15
]}

Higashiyama, Shigeki ^{[3
,4
,16
]}

Dan, Shingo ^{[5
]}

Pommier, Yves ^{[6
,7
]}

Murai, Junko ^{[1
,3
,4
,13
]}

机构：

[1] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata 9970017, Japan

[2] Meiji Pharmaceut Univ, Lab Mol & Cellular Biochem, Tokyo 2048588, Japan

[3] Ehime Univ, Proteo Sci Ctr, Toon, Ehime 7910295, Japan

[4] Ehime Univ, Grad Sch Med, Dept Biochem & Mol Genet, Toon, Ehime 7910295, Japan

[5] Japanese Fdn Canc Res, Canc Chemotherapy Ctr, Div Mol Pharmacol, Tokyo 1358550, Japan

[6] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20814 USA

[7] NCI, Lab Mol Pharmacol, NIH, Bethesda, MD 20814 USA

[8] Natl Canc Ctr Hosp East, Div Radiat Oncol & Particle Therapy, Chiba 2778577, Japan

[9] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Div Dev Pathol, Kashiwa, Chiba 2778577, Japan

[10] Niigata Univ, Brain Res Inst, Dept Neurosurg, Niigata 9518585, Japan

[11] Niigata Univ, Brain Res Inst, Dept Brain Tumor Biol, Niigata 9518585, Japan

[12] Niigata Univ, Brain Res Inst, Adv Treatment Neurol Dis Branch, Niigata 9518585, Japan

[13] Kyoto Univ, Radiat Biol Ctr, Grad Sch Biostudies, Kyoto 6068501, Japan

[14] Int Univ Hlth & Welf, Sch Healthcare Sci Narita, Dept Radiol Sci, Narita, Chiba 2860048, Japan

[15] Tokyo Metropolitan Inst Med Sci, Dept Microbiol & Cell Biol, Tokyo 1560057, Japan

[16] Osaka Int Canc Inst, Dept Oncogenesis & Tumor Regulat, Osaka 1030027, Japan

来源：

MOLECULAR CELL | 2025年 / 85卷 / 05期

关键词：

RNA-POLYMERASE I; CELL-LINES; HOMOLOGOUS RECOMBINATION; DNA-DAMAGE; CANCER; INHIBITION; SLFN11; TRANSCRIPTION; MAINTENANCE; NUCLEOLUS;

D O I：

10.1016/j.molcel.2025.01.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. SLFN11dependent 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.

引用

页数：30

共 47 条

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