Role of the ESCRT Complexes in Telomere Biology.
Eukaryotic 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.



Telomeres are the ends of eukaryotic chromosomes. They are necessary for the proper replication of the genome and protect the chromosomes from degradation. In a large-scale systematic screen for mutants that affect telomere length in yeast, we found that mutations in any of the genes encoding the ESCRT complexes, required for the formation of transport vesicles within the cell, cause telomere shortening. We carried out an analysis of the mechanisms disrupted in these mutants and found that they are defective for the ability to elongate short telomeres, probably due to faulty end processing. We discuss the significance of these findings and how they could be relevant to anticancer therapies.
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
Anna K
AK
Dieckmann
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel Aviv, Israel.
Vera
V
Babin
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel Aviv, Israel.
Yaniv
Y
Harari
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
Roland
R
Eils
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.|Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Jena, Germany.
Rainer
R
König
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany b.luke@imb-mainz.de martin@post.tau.ac.il.|Institute of Molecular Biology gGmbH, gefördert durch die Böhringer Ingelheim Stiftung, Mainz, Germany.
Brian
B
Luke
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel Aviv, Israel b.luke@imb-mainz.de martin@post.tau.ac.il.
Martin
M
Kupiec
D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D016681:Genome, Fungal; D006801:Humans; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059505:Telomere Homeostasis / Q000235:genetics* / Q000502:physiology; D059506:Telomere Shortening / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D019098:Telomerase