SIRT6 Regulates Telomere Movement in the Presence and Absence of Oxidative Damage

Oxidative damage to telomeres leads to telomere attrition and genomic instability and is likely a major cause of incomplete ends of replicated chromosomes. While the maintenance of telomere integrity requires restriction of telomere movement within the nucleus, increased telomere movement facilitates the repair of DNA damage at telomeres. Whether oxidative damage induces telomere movement and how telomere mobility is regulated remains poorly understood. Here, we show that oxidative damage triggers directional telomere movement, and that the human Sir2 homolog, Sirtuin 6 (SIRT6), is required for this process. This function of SIRT6 is mediated by the chromatin-remodeling protein SNF2H, which promotes chromatin decondensation in response to DNA damage. Interestingly, in undamaged cells, SIRT6 restricts telomere movement by stabilizing the shelterin protein TRF2 at telomeres. Together, our results suggest that SIRT6 plays two distinct roles in telomere movement in the presence and absence of oxidative damage through chromatin remodeling and sheltering stabilization, shedding new light onto the functions of SIRT6 in telomere structural maintenance.