Abstract
ABSTRACTEukaryotic chromosomal ends are protected by telomeres from fusion, degradation, and unwanted double-strand break repair events. Therefore, telomeres preserve genome stability and integrity. Telomere length can be maintained by telomerase, which is expressed in most human primary tumors but is not expressed in the majority of somatic cells. Thus, telomerase may be a highly relevant anticancer drug target. Genome-wide studies in the yeast Saccharomyces cerevisiae identified a set of genes associated with telomere length maintenance (TLM genes). Among the tlm mutants with short telomeres, we found a strong enrichment for those affecting vacuolar and endosomal traffic (particularly the endosomal sorting complex required for transport [ESCRT] pathway). Here, we present our results from investigating the surprising link between telomere shortening and the ESCRT machinery. Our data show that the whole ESCRT system is required to safeguard proper telomere length maintenance. We propose a model of impaired end resection resulting in too little telomeric overhang, such that Cdc13 binding is prevented, precluding either telomerase recruitment or telomeric overhang protection.
Highlights
Telomeres preserve genome stability and promote cell viability by protecting the eukaryotic chromosomal ends from fusion, degradation, and unwanted double-strand break repair events
Telomeres end in a 3= single-stranded DNA overhang that is recognized by the Cdc13-Stn1-Ten1 (CST) complex, which participates in telomere elongation and protects telomeres from unwanted DNA double-strand repair mechanisms, such as exonuclease 1 (Exo1)-mediated resection [2]
Based on our findings that 9 of 19 endosomal sorting complex required for transport (ESCRT) genes are significantly enriched within the subset of short tlm mutants (Fig. 1A), we examined the entire ESCRT family for its involvement in telomere length maintenance
Summary
Telomeres preserve genome stability and promote cell viability by protecting the eukaryotic chromosomal ends from fusion, degradation, and unwanted double-strand break repair events. The deletion of any TLM gene leads to either telomere shortening or lengthening. Among these genes, nine encode proteins of the endosomal sorting complex required for transport (ESCRT) system. The deletion of ESCRT proteins causes defects in chromosomal segregation in humans and in yeast, linking them to genomic stability and integrity [13]. Based largely on our genetic studies, we propose a model of impaired telomere end resection in ESCRT gene deletion mutants (referred to hereinafter as ⌬ESCRT mutants), resulting in too little telomeric overhang such that telomerase recruitment/elongation becomes compromised
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