Highlighted By: Huaiying Zhang, Carnegie Mellon University, Department of Biological Sciences
Preprint DOI: https://doi.org/https://doi.org/10.1101/2023.01.19.524780
This preprint has been assigned the following Badges:
- Dysfunctional telomeres in differentiated cells activate the ATM (ataxia telangiectasia-mutated)-dependent DNA damage response (DDR), leading to cell cycle arrest. However, the response of stem cells to telomere DNA damage remains poorly understood.
- The authors used inducible expression of the nuclease FokI fused to the telomere protein TRF1 in human induced pluripotent stem cells (iPSCs), to induce acute DNA double-strand breaks specifically at iPSC telomeres. The authors observed an ATR (ataxia telangiectasia and Rad3-related)-dependent DDR and telomerase-independent telomere lengthening. This lengthening occurred through the alternative lengthening of telomeres (ALT) pathway, which relies on homology-directed DNA repair.
- The study unveils a distinct response to telomere damage in iPSC cells and demonstrates that the ALT pathway, typically associated with telomerase-negative cancer cells, is active in telomerase-positive iPSC cells. These findings invite new hypotheses regarding the initiation of ALT-mediated cancer.
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