a, Overview of the DDR in response to TRF2 depletion in somatic cells. In response to uncapped telomeres, ATM kinase initiates DDR, leading to end-to-end fusions via the NHEJ pathway. b, POT1A, POT1B and BRD2ensure genomic stability in pluripotent mouse ES cells by inhibiting the activities of ATM and ATR kinases. As a result, mild DDR is not enough to cause end-to-end fusions. c, Increased expression of Zscan4—a cluster of two-cell-signature genes—might result in recombination-based telomere elongation. Alternatively, the ZSCAN4 -dependent inhibition of the ATM and ATR kinases at TRF2-depleted telomeres of ES cells ensures telomere stability.