TY - JOUR
T1 - Telomere erosion in human pluripotent stem cells leads to atr-mediated mitotic catastrophe
AU - Vessoni, Alexandre T.
AU - Zhang, Tianpeng
AU - Quinet, Annabel
AU - Jeong, Ho Chang
AU - Munroe, Michael
AU - Wood, Matthew
AU - Tedone, Enzo
AU - Vindigni, Alessandro
AU - Shay, Jerry W.
AU - Greenberg, Roger A.
AU - Batista, Luis F.Z.
N1 - Funding Information:
A.T. Vessoni was supported by the Philip W. Majerus, MD, Fellowship. M. Munroe is supported by the National Heart, Lung, and Blood Institute T32 Training Grant (HL007088-41). This research was supported by the National Cancer Institute (R01CA237263) to A. Vindigni and by the National Heart, Lung, and Blood Institute (1R01HL137793), the Alvin J. Siteman Cancer Center at Washington University in St. Louis, the American Cancer Society, the American Federation for Aging Research, the Longer Life Foundation, and the Center of Regenerative Medicine at Washington University in St. Louis to L.F.Z. Batista. The authors declare no competing financial interests.
Funding Information:
We thank J. Fitzpatrick, M. Shih, and P. Bayguinov (WUSTL Center for Cellular Imaging) for technical support; S. Stewart (WUSTL) for the EF1?-H2B-mApple lentivirus vector; and Genome Engineering and iPSC Center (GEIC-WUSTL) for assistance with gene editing. A.T. Vessoni was supported by the Philip W. Majerus, MD, Fellowship. M. Munroe is supported by the National Heart, Lung, and Blood Institute T32 Training Grant (HL007088-41). This research was supported by the National Cancer Institute (R01CA237263) to A. Vindigni and by the National Heart, Lung, and Blood Institute (1R01HL137793), the Alvin J. Siteman Cancer Center at Washington University in St. Louis, the American Cancer Society, the American Federation for Aging Research, the Longer Life Foundation, and the Center of Regenerative Medicine at Washington University in St. Louis to L.F.Z. Batista.
Publisher Copyright:
© 2021 Vessoni et al.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Cell cycle and division
KW - Cell death and autophagy
KW - Genetics
KW - Stem cells
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U2 - 10.1083/jcb.202011014
DO - 10.1083/jcb.202011014
M3 - Article
C2 - 33851958
AN - SCOPUS:85104309591
SN - 0021-9525
VL - 220
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 6
M1 - e202011014
ER -