TY - JOUR T1 - Telomere relocalization to the nuclear pore complex in response to replication stress JF - bioRxiv DO - 10.1101/2020.01.31.929059 SP - 2020.01.31.929059 AU - Alexandra M Pinzaru AU - Noa Lamm AU - Mike al-Kareh AU - Eros Lazzerini-Denchi AU - Anthony J Cesare AU - Agnel Sfeir Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/01/31/2020.01.31.929059.abstract N2 - Mutations in the telomere binding protein, POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we investigated the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR-interference and biotin-based proximity labelling, respectively. These screens revealed that replication stress is a major vulnerability in cells expressing mutant POT1 and manifest in increased mitotic DNA synthesis (MiDAS) at telomeres. Our study also unveiled a role for the nuclear pore complex (NPC) in resolving replication defects at telomeres. Depletion of NPC subunits in the context of POT1 dysfunction increased DNA damage signaling and telomere fragility. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity. ER -