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タイトル: | Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection |
著者: | Masamsetti, V. Pragathi Low, Ronnie Ren Jie Mak, Ka Sin O’Connor, Aisling Riffkin, Chris D. Lamm, Noa Crabbe, Laure Karlseder, Jan Huang, David C. S. Hayashi, Makoto T. Cesare, Anthony J. |
著者名の別形: | 林, 眞理 |
キーワード: | DNA replication Mitosis |
発行日: | 17-Sep-2019 |
出版者: | Springer Nature |
誌名: | Nature Communications |
巻: | 10 |
論文番号: | 4224 |
抄録: | Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution. |
著作権等: | © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
URI: | http://hdl.handle.net/2433/244141 |
DOI(出版社版): | 10.1038/s41467-019-12255-w |
PubMed ID: | 31530811 |
出現コレクション: | 学術雑誌掲載論文等 |
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