The nuclear pore complex prevents sister chromatid recombination during replicative senescence

Paula Aguilera, Jenna Whalen, Christopher Minguet, Dmitri Churikov, Catherine Freudenreich, Marie-Noëlle Simon () and Vincent Géli ()
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Paula Aguilera: Marseille Cancer Research Center (CRCM), U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes Equipe labellisée Ligue
Jenna Whalen: Tufts University
Christopher Minguet: Marseille Cancer Research Center (CRCM), U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes Equipe labellisée Ligue
Dmitri Churikov: Marseille Cancer Research Center (CRCM), U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes Equipe labellisée Ligue
Catherine Freudenreich: Tufts University
Marie-Noëlle Simon: Marseille Cancer Research Center (CRCM), U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes Equipe labellisée Ligue
Vincent Géli: Marseille Cancer Research Center (CRCM), U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes Equipe labellisée Ligue

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13979-5

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