Open AccessTelomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe
Author(s) -
Alexandre Teixeira Vessoni,
Tianpeng Zhang,
Annabel Quinet,
Ho-Chang Jeong,
Michael Munroe,
Matthew D. Wood,
Enzo Tedone,
Alessandro Vindigni,
Jerry W. Shay,
Roger A. Greenberg,
Luis Francisco Zirnberger Batista
Publication year - 2021
Publication title -
the journal of cell biology/the journal of cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.414
H-Index - 380
eISSN - 1540-8140
pISSN - 0021-9525
DOI - 10.1083/jcb.202011014
Subject(s) - telomere , biology , induced pluripotent stem cell , mitosis , microbiology and biotechnology , mitotic catastrophe , stem cell , senescence , dna damage , cell division , cell cycle , genetics , cell , embryonic stem cell , dna , gene
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.