Complex interactions between the DNA-damage response and mammalian telomeres

Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the 'end-protection problem' by inhibiting multiple DNA damage response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation.