Transient telomere uncapping triggers telomeric and subtelomeric rearrangements.

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Telomeres protect chromosome ends from DNA damage.
• Telomere uncapping threatens genome integrity.
• The Cdc13-Stn1-Ten1 complex normally prevents DNA damage signaling after telomere uncapping.

Purpose of the Study:

• To investigate the immediate consequences of transient telomere uncapping on genome stability.
• To identify the mechanisms and genetic factors involved in genomic rearrangements following telomere uncapping.

Main Methods:

• Utilized the temperature-sensitive cdc13-1 yeast mutant.
• Employed long-read sequencing to analyze genomic rearrangements.
• Investigated the role of homologous recombination factors (Rad52, Rad51, Rad59) and Pol32.

Main Results:

• Transient telomere uncapping induced extensive genomic rearrangements, including subtelomeric recombination and telomere elongation up to 10 kb.
• Observed Y' element dynamics, terminal duplications, and telomeric circle-mediated repeat amplification.
• Rearrangements required Rad52, Pol32, and partially Rad51/Rad59, occurring over multiple generations.
• Elongated telomeres conferred Rad52-dependent resistance to subsequent uncapping.

Conclusions:

• Transient telomere uncapping triggers significant genome instability via specific rearrangement pathways.
• Homologous recombination is crucial for resolving telomere uncapping-induced damage.
• Telomere elongation can serve as a protective mechanism against further telomere dysfunction.