Chromosome ends need to be protected from DNA-damage signalling and repair pathways to avoid aberrant repair events. However, senescence or loss of components of the so-called shelterin complex causes induction of a DNA-damage response at telomeres. Karlseder and colleagues now discover that prolonged mitotic arrest can also result in the formation of telomeric DNA-damage foci (Nat. Struct. Mol. Biol. 19, 387–394; 2012)

The authors discovered that introducing prolonged mitotic arrest by interfering with sister chromosome cohesion (by depletion of the cohesin subunit RAD21, sororin or shugoshin) or the mitotic spindle (by microtubule-targeted drugs or inhibition of the Eg5 kinesin), leads to an increase in telomere-associated DNA damage. The prolonged mitotic arrest was associated with the loss of telomeric 3´ overhangs and activation of the ATM kinase, similarly to what is observed after inactivation of the DNA repair protein TRF2. Indeed, TRF2 was reduced at telomeric repeats, and its forced expression reduced the formation of telomeric DNA-damage foci. Colcemid-treated cells, which were then released to allow mitosis to proceed, showed persistent foci in G1, leading to p53 activation and G1 phase arrest. Although it remains unclear exactly how prolonged mitotic arrest causes the removal of TRF2, the authors could show that the mitotic kinase Aurora B, but not the spindle assembly checkpoint, is required.

One implication of these results is that therapeutic drugs that induce mitotic arrest may ultimately cause aneuploidy due to telomeric deprotection.