1. Introduction
Telomeres serve two vital functions to eukaryotes. They act as a protective chromosome cap to distinguish natural chromosome ends from double stranded DNA breaks and to avoid inappropriate fusions of telomeric sequences, and they maintain chromosome length by adding DNA to the ends of chromosomes. Telomeres thus balance the loss of terminal DNA due to the inability of the replication machinery to completely replicate linear DNA molecules (Olovnikov, 1973; Watson, 1972). In many cases the newly replicated chromosome ends are resected to allow for the formation of a t-loop that helps to hide the tip (Griffith et al., 1999; Wellinger et al., 1996). Most eukaryotes elongate chromosome ends with a special reverse transcriptase, telomerase, that carries a specific RNA template with telomeric sequence (Greider, 1996). The telomerase enzyme repeatedly adds copies of the short telomeric DNA sequence to the chromosome end. While there is strict conservation of telomeric sequence repeat in most species, the repeat unit has changed over evolutionary time. Holotrichous ciliates, e. g.
Lack of the predominant telomeric sequence in a species does not, however, signify that telomerase-generated terminal sequences are missing. For example, the metazoan-type telomeric sequence is found in place of the plant sequence in
Although telomerase may have been the mechanism of telomere maintenance of the last common eukaryotic ancestor, it is not the only mechanism used to maintain chromosome length. Telomerase has been lost a few times in the evolution of plants and animals. During insect evolution, for example, telomerase has been lost at least six times. Here, we discuss telomere maintenance mechanisms that replaced telomerase in telomere length maintenance. In most cases the nature of the chromosome ends in organisms lacking telomerase is not known. In some species the telomerase-generated short telomeric repeat arrays have been replaced by tandem arrays of DNA sequences that look much like heterochromatin and can be elongated by copying information from one chromosome end to another, i. e. gene conversion. A completely different mechanism has been found in
2. Plants without telomerase
The plant telomeric sequence (TTTAGGG)n appears to be highly conserved in all phyla of the plant kingdom (Fuchs et al., 1995; Fuchs & Schubert, 1996; Richards & Ausubel, 1988). Nevertheless, in the order Asparagales the plant telomeric motif has been replaced with (TTAGGG)n but is still maintained by telomerase (Fajkus et al., 2005). In addition, three genera within the family Solanaceae appear to have lost both the canonical telomeric DNA motif as well as telomerase, which is required to maintain this motif.
2.1. The nightshade family
In the family Solanaceae the canonical plant telomeric repeat is replaced by a less conventional telomeric sequence that may be associated with a different compensation pathway. Detailed analysis of Solanaceae species revealed that although plant telomeric sequence is present in tobacco, tomato and other representatives of this family, the telomeric motif and telomerase activity are missing in the three closely related genera of
2.2. The onion family
Chromosome termini of the onion,
3. Animals without telomerase
In the case of animals, the lack of a telomerase system has been reported in a few insect species. The (TTAGG)
3.1. The silkworm
A highly interesting case of telomeres was revealed in another model organism, the silkworm,
3.2. Lower diptera
Telomerase has not been found in any dipteran species (Figure 1). As fossils for this order date to the middle Triassic period, it is possible that telomerase may have been lost as much as 225 million years ago. Nevertheless, Diptera as a group are very successful, accounting for some 10% of known animal species. Thus, loss of telomerase does not seem to have been a major impediment to survival. Replacement of short telomerase-generated repeats with long satellite sequences is reported in lower dipteran species. Chromosome tips of non-biting midges (genus
recombination mechanism involving these long blocks of complex repeat units (Biessmann & Mason, 1997; Cohn & Edstrom, 1992; Cohn & Edström, 1992; Nielsen & Edstrom, 1993). A situation has been observed in
3.3. Drosophila
Most of our information on the structure and maintenance of telomeres in
3.3.1. Drosophila melanogaster
Three distinct telomeric regions have been identified in
3.3.1.1. Telomeric retrotransposons
Studies on
As a group the HTT elements have characteristics that distinguish them from other retrotransposons (Figure 2A).
reverse transcriptase.
3.3.1.2. The terminal retrotransposon array
The three retrotransposons present in
As expected from the end replication problem, the broken chromosome ends recede. Erosion at these terminally deficient chromosomes was estimated at a constant rate of about 75 bp per sexual generation (Biessmann & Mason, 1988; Levis, 1989; Mikhailovsky et al., 1999). Considering the number of germline cell divisions, the rate of terminal erosion was estimated at 2-3 bp per chromosome end per cell cycle (Biessmann & Mason, 1988). This is formally equivalent to the degradation of an 8-12 nt RNA primer from the end of the lagging strand after each round of replication leaving a short 3' overhang (Biessmann et al., 1990a). In mammals telomere erosion is faster, in large part because chromosome ends are resected to produce relatively long 3' overhangs necessary for t-loop formation (Griffith et al., 1999; Wellinger et al., 1996). The slow rate of loss in
3.3.1.3. Transposition to elongate telomeres
To counter terminal erosion and maintain their length, telomeres must be elongated. The broken chromosome ends provide an entrée to study telomere elongation. Southern blots to monitor terminal fragment length at a broken chromosome end identified the addition of new sequence onto the terminal fragment at a frequency of about 1% per generation, with an average length for the added fragment of 6 kb (Biessmann et al., 1992a; Biessmann et al., 1990b). This averages out to an addition of 60 bp per generation, just enough to balance terminal erosion. It is important to note that the frequency of addition onto chromosome ends may be sensitive to different factors, including genetic background and possibly external conditions. Using genetic assays, two groups have identified stocks with much different frequencies of addition, possibly by as much as two orders of magnitude in either direction (Golubovsky et al., 2001; Savitsky et al., 2002; Savitsky et al., 2006). The new additions onto the receding chromosome ends were identified as
3.3.1.3.1. The transcription step
The first step in the process of retrotransposition is transcription of the transposable element (Figure 3). All three telomeric elements have unusual transcription patterns.
One appealing mechanism for controlling the length of the terminal retrotransposon array is to regulate transcription of these elements. Two forms of this mechanism have been proposed, but both have problems. First, it was noted that transgenes inserted into subtelomere regions are repressed and variegate (Cryderman et al., 1999; Roseman et al., 1995). In addition, TAS arrays can silence
3.3.1.3.2. Telomere targeting
After transcription the RNA is transported into the cytoplasm and translated. The
3.3.1.3.3. Consequences of transposition on terminal array structure
Given the constant erosion of chromosome ends and the stochastic addition of transposon sequences to the same ends, one might expect that the terminal retrotransposon array would be very dynamic, constantly changing in length and composition. We have found this to be true using a genetic assay for the number of transposons at a specific telomere (Golubovsky et al., 2001; Mason et al., 2003b). One consequence of this turnover is that the transposon elements at the terminus are younger than those nearer to TAS. Virtually complete terminal arrays have been identified in overlapping BAC clones (Abad et al., 2004a). The age differential can be seen in the distribution of transposable elements that do not specifically target the chromosome end. These transposons are found primarily in the older, proximal portion of the terminal array (Pardue & DeBaryshe, 2008). Turnover in the younger, distal portion of array the removes evidence of these transposons. Newly transposed
The 5' and 3' UTRs of
3.3.1.4. Recombination to elongate telomeres
Transposition is not the only mechanism for telomere elongation in
Although experiments using broken chromosome ends to monitor telomere elongation use an artificial system of telomere maintenance, it is assumed that the telomere elongation mechanisms identified in these experiments also work at the ends of long retrotransposon arrays. Extensions of long terminal arrays by individual transposition events or short gene conversion tracks cannot be monitored genetically or molecularly. If, however, genetic factors cause an imbalance between elongation and erosion, terminal retrotransposon arrays may grow or shrink. This can be measured cytologically by
Mutations have been identified in three genes that cause terminal transposon array length to increase. Telomere length is sensitive to HP1 concentration, as mutations in the gene encoding this protein lead to an increase in
increased transcription increases transposition of the telomere-specific elements, and
disruption of the cap by decreasing one of its component proteins increases accessibility of the transposons.
Our data (RCF and JMM, unpublished data), however, suggest that neither is true. Other mutations associated with increased
3.3.2. Drosophila virilis
The DNA sequence of individual
Searching for telomeric retrotransposons in more distantly related species presents a problem because of the extensive sequence divergence. Only the most conserved part of the
There are significant differences between the telomere specific elements in
4. Conclusion
Although rare, telomerase has been lost several times in plants and animals. In some cases, such as Diptera, telomerase was lost in the distant past, and the descendents of this event have thrived and diversified. This raises the possibility that, once established, organisms with noncanonical mechanisms of telomere maintenance may not be at a severe selective disadvantage. How, then, do we account for the paucity of organisms lacking telomerase? One possibility is that there is a strong selective barrier to the loss of telomerase-generated DNA motifs. Binding of the shelterin protein complex necessary for the protection of chromosome ends depends on sequence-specific binding. The shelterin components TRF1 and TRF2 in particular recognize the double stranded telomeric motif, while POT1 recognizes the single stranded form (Palm & de Lange, 2008). Thus, in most cases loss of telomerase results in loss of the telomeric motif, followed by loss of the chromosome cap, massive chromosome rearrangement and death. If, however, telomeric attachment of the cap complex in some lineages does not depend strongly on a specific DNA sequence, loss of the telomeric motif might not have the same catastrophic consequences. This might explain why insects have lost telomerase and the canonical arthropod-type telomeric sequence multiple times (Figure 1). This hypothesis assumes the existence of an effective backup mechanism that can replace the canonical telomerase system. Alternatively, it may be misleading to suggest that loss of telomerase occurred only in the small number of organisms already reported. There may be, for example, cases similar to
Recombination seems like a ready backup mechanism for telomere maintenance by transferring information from one DNA strand to another, because it is widely used by eukaryotes both during meiotic recombination and as a means of repairing DNA damage (Heyer et al., 2010). Some organisms are known to use recombination to maintain the canonical telomeric DNA sequence in the absence of telomerase. In
Acknowledgments
We thank František Marec, Jan Zrzavý and Sailesh Surapureddi for valuable comments on the manuscript. The authors were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, the MOBITAG project (Reg. No. 229518 of EU program FP7-REGPOT-2008-1) and the Institute of Entomology project Z50070508
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