Abstract
Telomeres are the terminal structures at the ends of linear chromosomes that represent a solution to the end replication problem. Specific binding of the six-protein subunit complex shelterin to telomeric, repetitive TTAGGG DNA sequences contributes to the stable architecture and maintenance of telomeres. Proteins involved in the DNA damage response are also localized at telomeres, and play a role in the surveillance and maintenance of telomere integrity. The enzyme responsible for telomere extension is telomerase, a ribonucleoprotein with reverse transcriptase activity. In the absence of telomerase, telomeres shorten to a length threshold that triggers the DNA damage response and replicative senescence. Here, we will summarize the latest findings concerning vertebrate telomere structure and epigenetics, and we present data regarding the impact of short telomeres upon cell signaling. In particular, in murine embryonic stem cells lacking telomerase, we found that distribution of cytosolic/nuclear β-catenin, a key component of the Wnt signaling pathway, changes when telomeres become critically short. We discuss implications and future perspectives of the effect of epigenetic modifications and/or conformational changes of telomeres on cell metabolism and signaling networks. Such an analysis may unveil potential therapeutic targets for pathologies like cancer, where the integrity of telomeres is altered.
Highlights
TELOMERE STRUCTURE IN VERTEBRATES Telomeres are the structures at the ends of chromosomes that protect them from end-to-end fusions and solve the problem of end replication, i.e., the loss of genetic material due to inherent limitations in the DNA replication process (Blackburn, 1991)
We queried whether the abundance of key signaling factors would be altered in the presence of short telomeres, and focused our investigation on β-catenin, a critical component of the Wnt signaling network that controls cell proliferation and differentiation (Clevers and Nusse, 2012). β-catenin distribution and post-translational modifications were compared in mTert−/− at late passage (>60 passages) and wild-type ESC at a similar passage number (Figure 2A)
We observed that cytosolic β-catenin was significantly more abundant in mTert−/− ESC with critically short telomeres compared to wild-type cells (Figure 2B, Student’s t -test P = 0.003) while the total content remained unchanged (Figure 2B, P = 0.968)
Summary
TELOMERE STRUCTURE IN VERTEBRATES Telomeres are the structures at the ends of chromosomes that protect them from end-to-end fusions and solve the problem of end replication, i.e., the loss of genetic material due to inherent limitations in the DNA replication process (Blackburn, 1991). Telomeres are protected and regulated by a specific hexaprotein complex, called shelterin (i.e., TRF1, TRF2, RAP1, TIN2, POT1, TPP1) (Figure 1A), and additional non-telomere specific proteins that are implicated in the cellular DNA damage response (de Lange, 2005; Longhese, 2008). Shelterin inhibits the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)-dependent DNA damage response, non-homologous end joining and homologous recombination DNA repair pathways, and resection by 5 -exonucleases (Sfeir and de Lange, 2012). Some of these activities are specific to shelterin whereas other activities that inhibit non-homologous end joining and resection are supported by other telomere-associated proteins such as Ku70/80 and 53BP1, respectively (Sfeir and de Lange, 2012). The extension of telomeres occurs during S-phase and telomerase extends the shortest telomeres preferentially (Hemann and Greider, 1999; Samper et al, 2001; Erdmann et al, 2004; Stern and Bryan, 2008)
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