Abstract
The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. Here, we uncover that fusing a DNA binding domain to the NPC basket protein Nup1 reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup1 modification also impairs the relocalization to the NPC of expanded CAG/CTG triplet repeats. Strikingly, telomerase negative cells bypass senescence when expressing this Nup1 modification by maintaining a minimal telomere length compatible with proliferation through rampant unequal exchanges between sister chromatids. We further report that a Nup1 mutant lacking 36 C-terminal residues recapitulates the phenotypes of the Nup1-LexA fusion indicating a direct role of Nup1 in the relocation of stalled forks to NPCs and restriction of error-prone recombination between repeated sequences. Our results reveal a new mode of telomere maintenance that could shed light on how 20% of cancer cells are maintained without telomerase or ALT.
Highlights
The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage
In order to address the role of the NPC in controlling telomere recombination during replicative senescence[35], we constructed a strain in which Nup[1] was C-terminally tagged at its native locus with the DNA binding protein LexA (Fig. 1a)
Our initial idea was to develop an assay to tether genomic regions tagged with LexA-binding sites to the NPC in telomerase-negative cells
Summary
The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. We uncover that fusing a DNA binding domain to the NPC basket protein Nup[1] reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup[1] modification impairs the relocalization to the NPC of expanded CAG/CTG triplet repeats. Telomeres are nucleoprotein structures that protect the ends of linear eukaryotic chromosomes against degradation, end-to-end fusions and homologous recombination (HR). They consist of G-rich repetitive DNA sequences with a terminal 3′ single-strand overhang[1]. When telomeres become critically short, unprotected telomeres elicit a DNA damage response (DDR), recruit Mec1ATR and activate a permanent G2/M arrest[11,12] leading to replicative senescence
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