The Human Telomeric Proteome During Telomere Replication

Summary Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND, which enables purification of proteins that associate with telomeres specifically during replication. We identify in addition to the core replisome a large number of proteins that associate with telomere replication forks and validate their importance. We find that POT1 is depleted, whereas histone H1 is specifically enriched, at telomere replication forks. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.