期刊
AUTOPHAGY
卷 17, 期 3, 页码 796-813出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1764727
关键词
Chromosomal instability; chromosomes segregation; lysosome; mitosis; selective autophagy; toroidal nucleus
类别
资金
- Agencia de Gestio d'Ajuts Universitaris i de Recerca [2017SGR1743]
- H2020 Marie Sklodowska-Curie Actions [799000]
- Instituto de Salud Carlos III [RD12/0036/0049]
- Ministerio de Ciencia, Innovacion y Universidades [IJCI-2015-24716]
- Ministerio de Economia, Industria y Competitividad, Gobierno de Espana [SAF2017-85561-R]
- Ministerio de Educacion, Cultura y Deporte [FPU13/05400]
- National Institutes of Health [RO1-HL125353]
- Mayo Clinic/National Institutes of Health [5-T32-CA217836-02]
- Marie Curie Actions (MSCA) [799000] Funding Source: Marie Curie Actions (MSCA)
This study demonstrates the essential role of lysosome-dependent degradation in preventing chromosomal instability during mitotic transition. Disruption of lysosomes prolongs mitotic timing and induces mitotic errors, leading to chromosomal instability. Furthermore, the study identifies potential lysosomal targets in mitotic cells and highlights the importance of proper lysosomal function in maintaining genomic stability.
Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability.
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