Rad6-Bre1 mediated histone H2Bub1 protects uncapped telomeres from exonuclease Exo1 in Saccharomyces cerevisiae.

Histone H2B lysine 123 mono-ubiquitination (H2Bub1), catalyzed by Rad6 and Bre1 in Saccharomyces cerevisiae, modulates chromatin structure and affects diverse cellular functions. H2Bub1 plays roles in telomeric silencing and telomere replication. Here, we have explored a novel role of H2Bub1 in telomere protection at uncapped telomeres in yku70Δ and cdc13-1 cells. Deletion of RAD6 or BRE1, or mutation of H2BK123R enhances the temperature sensitivity of both yku70Δ and cdc13-1 telomere capping mutants. Consistently, BRE1 deletion increases accumulation of telomeric single-stranded DNA (ssDNA) in yku70Δ and cdc13-1 cells, and EXO1 deletion improves the growth of yku70Δ bre1Δ and cdc13-1 bre1Δ cells and decreases ssDNA accumulation. Additionally, deletion of BRE1 exacerbates the rate of entry into senescence of yku70Δ mre11Δ cells with telomere defects, and increases the recombination of subtelomeric Y' element that is required for telomere maintenance and survivor generation. Furthermore, Exo1 contributes to the abrupt senescence of yku70Δ mre11Δ bre1Δ cells, and Rad51 is essential for Y' recombination to generate survivors. Finally, deletion of BRE1 or mutation of H2BK123R results in nucleosome instability at subtelomeric regions. Collectively, this study provides a mechanistic link between H2Bub1-mediated chromatin structure and telomere protection after telomere uncapping.