TERRA expression triggers telomere elongation

 TERRA expression triggers telomere elongation
Abstract
Telomeres are the regions at the end of chromosomes that protect them from degradation.
Telomeric DNA damage was shown to induce cellular senescence and programmed cell death
(apoptosis). Telomere shortening is associated with aging. On the other hand, activity of the
enzyme that extends telomeres (telomerase) was found in almost all human tumours. The
absence of telomerase activity in most human cells is a necessary condition for maintaining
normal tissue homeostasis.
For years, telomeres were considered to be transcriptionally silent. That is why the recent finding
of telomeric repeat-containing RNA (TERRA) transcribed at chromosome ends stunned the
scientific world. It is now shown that TERRA molecules play a crucial role in telomere maintenance
and regulation of telomerase activity. Cusanelli et al. suggested that TERRA expression may
represent a signal induced by short telomeres to trigger telomerase recruitment and subsequent
telomere elongation. Altered expression of TERRA is associated with genome instability, which
can lead to cellular malignization or senescence. Since biological functions of TERRA are still
unclear, finding out the molecular mechanisms of TERRA biogenesis and functioning will require
a significant effort. It will advance our understanding of telomere-related diseases, cancer and
aging.
Telomeres are the ends of eukaryotic chromosomes, which are associated with proteins
to protect the DNA ends from being recognized as double-strand breaks (DSBs). The end
replication problem with following processing by exonucleases is the mechanism of telomeres
shortening at each cell division. Loss of telomere length below a critical threshold leads to cellular
senescence, apoptosis, or genome instability. Telomerase can solve these problems. It is a
reverse transcriptase that contains integral RNA moiety. This RNA will serve as a template for
lengthening telomeric 3’ overhangs via reverse transcription into telomeric DNA repeats
(Feuerhahn et al., 2010). In Saccharomyces cerevisiae (budding yeast), telomerase is
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Sample: Molecular Biology - TERRA and Telomere Elongation
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constitutively expressed, and its activity is differentially regulated to extend the shortest
telomeres (Cusanelli et al., 2013). Most of the human somatic cells are telomerasenegative(Feuerhahn et al., 2010).
Telomeres are heterochromatic structures and were considered to be transcriptionally
silenced. However, recent studies have demonstrated that telomeres are transcribed into
TElomeric Repeat-containing RNA (TERRA). A lot of scientific groups are trying to define the
functions of TERRA molecules. Their investigations allowed to suggest that TERRA molecules
regulate telomere structural maintenance and heterochromatin formation, inhibit telomerase
activity, promote telomere capping after DNA replication. However, biological functions of TERRA
are still unclear (Feuerhahn et al., 2010).
Alterations in TERRA levels were observed in cancer cells and Immunodeficiency,
Centromeric region instability, Facial anomalies (ICF) syndrome cells. A number of research
groups have tried to elucidate the possible function of TERRA in malignant growth. However, the
data obtained are controversial. First, the levels of TERRA molecules were reported to be
decreased in human cancers compared with normal tissues. Later, elevated levels of TERRA were
detected in stomach, lung, colon, and ovary cancers compared with normal tissues. Besides, the
transcription of some telomeres into TERRA has been inhibited, while the transcription of others
has been enhanced, resulting in decreased or increased levels of TERRA transcripts that
originated from different telomeres in cancers compared with normal tissues. A possible
explanation for such discrepancy could be the difference between TERRA levels in various cancer
types, and the difference between tumours and cancer cell lines (Cusanelli & Chartrand, 2014).
Disturbances of TERRA expression have been associated with cellular senescence. It is a
powerful tumour suppressor mechanism. However, results obtained from different research
groups are conflicting. Caslini et al. demonstrated a decrease in TERRA expression level in human
primary fibroblasts throughout the passages. It was correlated with a decrease in H3K4
methylation, which refers to transcriptionally active telomeres. In contrast to their results, in the
study conducted by Thijssen et al., no difference in TERRA levels was observed in late versus early
passage human primary fibroblasts. It was correlated with the repressed state of telomeres
during senescence. In mutant budding yeast with lack of telomerase activity, TERRA levels are
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elevated. Balk et al. showed that TERRA-DNA hybrids could help to maintain telomere length via
telomere r