Mechanism of end protection in stem cells

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When telomeres become critically short, they become dysfunctional and elicit activation of the DNA damage response pathway at chromosome ends. Cells with dysfunctional telomeres can either undergo programmed cell death, enter into an irreversible cell cycle arrest, or accumulate genome instability and eventually transform into an aggressive cancer cell. Using conditional deletion of shelterin components, we have shown that the differentiation status has a major impact on the cellular response to telomere dysfunction (Lazzerini Denchi et al., 2006; Lobanova et al., 2017; Pinzaru et al., 2016). We have demonstrated that, in response to the same type of genetic manipulation, certain cell types accumulate genome instability and eventually develop into aggressive tumors. In contrast, others never overcome the proliferation barrier imposed by telomere dysfunction (Lobanova et al., 2017; Pinzaru et al., 2016). Given the importance of telomere-driven genome instability in the development of cancer, these data highlight a significant gap in knowledge in a critical tumor-initiating process. Our ongoing work aimed at understanding the connection between telomere dysfunction and the differentiation status revealed that, unexpectantly, pluripotent embryonic stem cells (ESCs) could survive in the absence of essential shelterin components. This unexpected finding opens a set of outstanding questions regarding the mechanism of telomere protection in pluripotent stem cells