Telomeres cap the extremities of linear chromosomes and prevent their detection as DNA damage. Telomere uncapping poses a profound threat to genome integrity, yet the immediate consequences of transient uncapping remain unclear. In Saccharomyces cerevisiae, the Cdc13-Stn1-Ten1 complex limits resection, preventing DNA damage checkpoint activation. Here, using the temperature-sensitive cdc13-1 allele, we demonstrate that transient telomere uncapping rapidly induces extensive genomic rearrangements despite a functional DNA damage checkpoint. Two distinct rearrangement signatures are observed in surviving cells: recombination of the subtelomeric region mostly involving the Y' elements, and massively elongated telomeres up to 10 kb, a ~ 30-fold increase. Long-read sequencing evidences Y' element losses/amplifications, terminal duplications, and telomeric-circle-driven amplifications of telomere repeats. Rearrangements unfold over multiple generations and require the homologous recombination factor Rad52, the Polδ subunit Pol32, and partially Rad51 and Rad59. Remarkably, survivors with elongated telomeres demonstrate a robust Rad52-dependent resistance to subsequent telomere uncapping. Our findings provide novel insights into the consequences of transient telomere uncapping for genome stability, a process that might contribute to subtelomere and telomere dynamics and evolution.

• PMID: 41703072
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Journal Article

Authors

Dudragne L, Garrido C, Ilioaia O, Bernardes JS, Xu Z

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