RT Journal Article
SR Electronic
T1 Telomere relocalization to the nuclear pore complex in response to replication stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.31.929059
DO 10.1101/2020.01.31.929059
A1 Alexandra M Pinzaru
A1 Noa Lamm
A1 Mike al-Kareh
A1 Eros Lazzerini-Denchi
A1 Anthony J Cesare
A1 Agnel Sfeir
YR 2020
UL http://biorxiv.org/content/early/2020/01/31/2020.01.31.929059.abstract
AB 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.