Telomere and telomerase modulation by the mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex

Telomeres, 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 [1-3]. 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.