Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe
| Autor: | Annabel Quinet, Enzo Tedone, Tianpeng Zhang, Michael Munroe, Ho-Chang Jeong, Luis F.Z. Batista, Alessandro Vindigni, Roger A. Greenberg, Alexandre T. Vessoni, Jerry W. Shay, Matthew D. Wood |
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| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
Cellular differentiation Mitosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Biology Cell cycle phase 03 medical and health sciences 0302 clinical medicine Report Genetics Humans Induced pluripotent stem cell Mitotic catastrophe 030304 developmental biology 0303 health sciences Stem Cells Cell Cycle Cell Biology Telomere Cell cycle Aneuploidy Cell Death and Autophagy Cell biology 030220 oncology & carcinogenesis Tumor Suppressor Protein p53 Stem cell Cell Cycle and Division DNA Damage |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.202011014 |
| Popis: | Vessoni et al. demonstrate telomere shortening leads to a unique DDR response in human pluripotent stem cells. Unlike terminally differentiated cells, telomere shortening induces formation of single-stranded DNA telomere overhangs in hPSCs, which activate ATR signaling and lead to mitotic catastrophe and p53-dependent cell death. It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts. |
| Databáze: | OpenAIRE |
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