SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis
Akane Ogawa, Keiichi Izumikawa, Sota Tate, Sho Isoyama, Mori Masaru, Kohei Fujiwara, Soyoka Watanabe, Takayuki Ohga, Ukhyun Jo, Daiki Taniyama, Shojiro Kitajima, Soichiro Tanaka, Hiroshi Onji, Shun‐Ichiro Kageyama, Gaku Yamamoto, Hitoshi Saito, Tomoko Morita, Masayasu Okada, Manabu Natsumeda, Masami Nagahama, Junya Kobayashi, Akihiro Ohashi, Hiroyuki Sasanuma, Shigeki Higashiyama, Shingo Dan, Yves Pommier, Junko Murai
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.