Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1

Rekha Rai (), Kevin Biju, Wenqi Sun, Tori Sodeinde, Amer Al-Hiyasat, Jaida Morgan, Xianwen Ye, Xueqing Li, Yong Chen and Sandy Chang ()
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Rekha Rai: Yale University School of Medicine
Kevin Biju: Yale University School of Medicine
Wenqi Sun: Chinese Academy of Sciences
Tori Sodeinde: Yale University School of Medicine
Amer Al-Hiyasat: Yale University School of Medicine
Jaida Morgan: Yale University School of Medicine
Xianwen Ye: University of Chinese Academy of Sciences
Xueqing Li: Chinese Academy of Sciences
Yong Chen: Chinese Academy of Sciences
Sandy Chang: Yale University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Double-strand breaks (DSBs) due to genotoxic stress represent potential threats to genome stability. Dysfunctional telomeres are recognized as DSBs and are repaired by distinct DNA repair mechanisms. RAP1 and TRF2 are telomere binding proteins essential to protect telomeres from engaging in homology directed repair (HDR), but how this occurs remains unclear. In this study, we examined how the basic domain of TRF2 (TRF2B) and RAP1 cooperate to repress HDR at telomeres. Telomeres lacking TRF2B and RAP1 cluster into structures termed ultrabright telomeres (UTs). HDR factors localize to UTs, and UT formation is abolished by RNaseH1, DDX21 and ADAR1p110, suggesting that they contain DNA-RNA hybrids. Interaction between the BRCT domain of RAP1 and KU70/KU80 is also required to repress UT formation. Expressing TRF2∆B in Rap1–/– cells resulted in aberrant lamin A localization in the nuclear envelope and dramatically increased UT formation. Expressing lamin A phosphomimetic mutants induced nuclear envelope rupturing and aberrant HDR-mediated UT formation. Our results highlight the importance of shelterin and proteins in the nuclear envelope in repressing aberrant telomere-telomere recombination to maintain telomere homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-37761-w

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