Epigenetic Telomere Protection by Drosophila DNA Damage Response Pathways

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Abstract
Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms. Organisms with linear chromosomes must distinguish between the naturally occurring ends of chromosomes (telomeres) and chromosome breaks due to DNA damage. Many eukaryotic cells use DNA binding proteins that specifically recognize telomeric DNA sequences to protect telomeric DNA ends from the inappropriate action of DNA repair enzymes. In Drosophila melanogaster, however, chromosomes that lack telomere-specific sequences can be isolated and stably maintained. Thus, telomere protection can be inherited via a sequence-independent or epigenetic mechanism. Oikemus et al. demonstrate that two groups of genes that help cells respond to DNA damage are also required to localize a telomere protection protein to chromosome ends. Two experiments are described to support the model that these DNA damage detection genes help maintain telomere protection regardless of telomere sequence. First, mutations in these genes lead to loss of telomere protection without loss of telomeric DNA. Second, telomeres that lack all telomere-specific sequences still require these genes for protection. Combined, these experiments suggest that recognition of DNA ends is required for sequence-independent protection of Drosophila melanogaster telomeres. Since the same genes also promote telomere protection in yeast, plants, and mammals, these observations may be relevant to chromosome function in many organisms.