Publication

Telomeric Repeat Containing RNAs and the Response to Telomere Deprotection in Saccharomyces Cerevisiae

Andrea Bernardo Panza
2012
EPFL thesis
Abstract

Telomeres are the DNA/RNA/protein structures at the end of linear eukaryotic chromosomes, which protect them against the DNA damage repair machinery, preventing chromosome end-to-end fusions and aberrant recombination. Moreover, telomeres compensate for the erosion that occurs at every cycle of DNA replication maintaining telomere length through the action of the telomerase reverse transcriptase. Even if telomeres have many features in common with heterochromatic DNA, they have been shown to be transcribed into telomeric repeat-containing RNA (TERRA) both in vertebrates and plants. In the first part of this work we demonstrate that TERRA expression is conserved in the yeast Saccharomyces cerevisiae. Moreover, TERRA is transcribed by RNA polymerase II, it is polyadenylated and its levels in wild type cells are maintained low through the action of the 5’ to 3’ RNA exonuclease Rati. Indeed cells harboring the thermosensitive mutant allele ratl-1 accumulate high levels of TERRA even at semipermissive temperature. Moreover, ratl-1 mutant cells display a telomere shortening phenotype that is rescued by RNase H overexpression, indicating that DNA/RNA hybrids, which can accumulate in this mutant, inhibit the normal telomere maintenance. In the second part of this work we tried to define TERRA function(s) in response to telomere alterations in yeast cells. We observed that TERRA increases during senescence and survivor formation in est2A mutant cells, which undergo through telomere shortening due to telomerase deletion. The observed increase in TERRA does not require the recombination machinery. Moreover, though TERRA levels are not altered by global DNA damage, they are raised in cdcl3-l, stnl-13 and ku70A mutants, which display telomere resection and DNA damage checkpoint activation at restrictive temperature, suggesting a specific role for TERRA in response to telomere alterations. Since the TERRA increase in telomere deprotection-mutants is suppressed by the deletion of either the 5’ to 3’ exonuclease EXOl or one of the checkpoint factors MEC1, TEL1 and RAD9, we suggest that TERRA is part of a specific checkpoint response, which is induced upon telomere resection. Finally, since est2A cells harboring the ratl-1 mutation display a prolonged senescence phenotype, we suspect a role for TERRA in telomere protection and in particular in preventing telomeric recombination.

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Related concepts (34)
Telomere
A telomere (ˈtɛləmɪər,_ˈtiːlə-; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double-strand break.
Telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres. Telomerase is a reverse transcriptase enzyme that carries its own RNA molecule (e.
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.
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