# Transient telomere uncapping triggers telomeric and subtelomeric rearrangements

## TL;DR

This study shows that brief telomere uncapping in yeast causes major genomic changes, including telomere elongation and subtelomeric rearrangements.

## Contribution

The study reveals two distinct rearrangement signatures caused by transient telomere uncapping and their dependence on homologous recombination factors.

## Key findings

- Transient telomere uncapping leads to subtelomeric rearrangements involving Y’ elements and telomere elongation up to 10 kb.
- Rearrangements require Rad52, Pol32, and partially Rad51 and Rad59 for their formation.
- Telomere elongation is associated with telomeric-circle-driven amplification and Rad52-dependent resistance to future uncapping.

## Abstract

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.

Transient telomere uncapping causes extensive genomic rearrangements at subtelomeres and telomeres, including telomeric-circle-mediated telomere elongation.

Transient telomere uncapping leads to two distinct rearrangement signatures, one involving the subtelomeric Y’ element, the other characterized by telomere elongation.Rearrangements unfold over multiple generations and require homologous recombination factors.A signature of t-circle-mediated amplification is associated with telomere elongation.

Transient telomere uncapping leads to two distinct rearrangement signatures, one involving the subtelomeric Y’ element, the other characterized by telomere elongation.

Rearrangements unfold over multiple generations and require homologous recombination factors.

A signature of t-circle-mediated amplification is associated with telomere elongation.

Transient telomere uncapping causes extensive genomic rearrangements at subtelomeres and telomeres, including telomeric-circle-mediated telomere elongation.