Telomere and Telomerase Modulation by the Mammalian Rad9/Rad1/Hus1 DNA-Damage-Checkpoint Complex

SummaryTelomeres, the termini of linear chromosomes, are exceptional in that they are DNA ends that do not normally trigger a DNA-damage response (DDR) and are compatible with normal cellular proliferation. Mammalian telomeres are nevertheless a physiological substrate of the DDR apparatus, as shown by the fact that the inactivation of genes encoding certain DDR factors results in telomere dysfunction 1, 2 and 3. However, how DDR factors are integrated with telomere physiology, including telomere length regulation by the specialized reverse transcriptase telomerase, is still largely unclear. Here we report that the mammalian Rad9/Rad1/Hus1 (911) checkpoint complex, which localizes to sites of genome damage and promotes DDR signaling [4], is an integral component of the telomere in human and mouse cells. By the use of quantitative telomere-length measurements, we demonstrate severe telomeric shortening in both Hus1-deficient mouse embryonic fibroblasts and thymocytes from conditional Hus1-knockout mice. We also show that 911 is found in association with catalytically competent telomerase in cell lysates and is a positive regulator of its DNA polymerase activity. These findings identify an unanticipated function for the 911 checkpoint complex at telomeres in mammals and provide a mechanistic link between the activity of DNA-damage-checkpoint proteins and the telomere-maintenance machinery.