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At least 19 recordsLinked to original sources

PubMed2004

Genetic dissection of the Kluyveromyces lactis telomere and evidence for telomere capping defects in TER1 mutants with long telomeres.

In the yeast Kluyveromyces lactis, the telomeres are composed of perfect 25-bp repeats copied from a 30-nucleotide RNA template defined by 5-nucleotide terminal repeats. A genetic dissection of the K. lactis telomere was performed by using mutant telomerase RNA (TER1) alleles to incorporate mutated telomeric repeats. This analysis has shown that each telomeric repeat contains several functional regions, some of which may physically overlap. Mutations in the terminal repeats of the template RNA typically lead to telomere shortening, as do mutations in the right side of the Rap1p binding site. Mutations in the left half of the Rap1p binding site, however, lead to the immediate formation of long telomeres. When mutated, the region immediately 3' of the Rap1p binding site on the TG-rich strand of the telomere leads to telomeres that are initially short but eventually undergo extreme telomere elongation. Mutations between this region and the 3' terminal repeat cause elevated recombination despite the presence of telomeres of nearly wild-type length. Mutants with highly elongated telomeres were further characterized and exhibit signs of telomere capping defects, including elevated levels of subtelomeric recombination and the formation of extrachromosomal and single-stranded telomeric DNA. Lengthening caused by some Rap1 binding site mutations can be suppressed by high-copy-number RAP1. Mutated telomeric repeats from a delayed elongation mutant are shown to be defective at regulating telomere length in cells with wild-type telomerase, indicating that the telomeric repeats are defective at telomere length regulation.

Binding Sites↗

PubMed1998

Estimation of the amount of telomere molecules in different human age groups and the telomere increasing effect of acupuncture and shiatsu on St.36, using synthesized basic units of the human telomere molecules as reference control substances for the bi-digital O-ring test resonance phenomenon.

It is well established that the telomeres at the ends of chromosomes are composed of long arrays of (TTAGGG)n x (CCCTAA)n that form a nucleoprotein complex required for the replication and protection of chromosome ends. Throughout the cell cycle, telomeres also contain a protein component related to the proto-oncogene Myb that is known as TRF1 (telomere TTAGGG repeat binding factor 1) that binds to the duplex array of TTAGGG repeats in the telomere. Previous studies have shown that TRF1 appears to play a role in controlling the length of telomeres by acting as an inhibitor of telomerase. The amount of each of the TRF1(C-19) & TRF1(N-19) was identical to the amount of telomere of the same organ of the same apparently normal individual. Using synthesized basic unit of TTAGGG, as well as CCCTAA, as separate reference control substances for the Bi-Digital O-Ring Test of Resonance Phenomenon between 2 identical substances, we were able to non-invasively measure the approximate amount of TTAGGG and CCCTAA units, in both normal and cancerous human cells. We examined about 30 apparently normal subjects (both Asian and Caucasian in both sex). The subjects' ages ranged from infancy to 76 years. Each subject was first examined using TTAGGG as a control substance and then examined using CCCTAA as a control substance. The amount of telomere in various cancer tissues are almost always higher than that of normal tissue of the same organ. The measured amounts of both TTAGGG and CCCTAA were found to be in an average of 1500-1600 ng for human fetus or infancy and decreased with the advance of age in both sex with the exception of the heart, brain, eyes (retina), testes, and ovaries, which usually remain at the level of the infant, or reduced very little. Individuals in the same age group had a similar range of amounts of both TTAGGG and CCCTAA in the same organ of the same individual, (except for those with unusually low telomeres often had chronic degenerative diseases, and those who had exceptionally high telomere levels often had excellent physical conditions or mental acumen). The amounts of measured TTAGGG and CCCTAA molecules before and after acupuncture on St. 36 in adenocarcinomas and small cell carcinoma coexisting in the lung of a 54-yr.-old Asian male were: telomere in adenocarcinoma decreased from 950 ng to 750 ng and telomere in small cell carcinoma decreased from 770 ng to 600 ng. When the cancer treatment is effective, the amount of telomere is reduced towards the value of the normal internal organ. We found that acupuncture on St.36 on apparently normal subjects increased the telomere levels up to a maximum of more than 2 times their telomere levels prior to the treatment, depending on the method of treatment, but frequently increases were between 60% to 100%. Strong Shiatsu performed on St. 36 produced a somewhat lesser effect than acupuncture. We also determined the amounts of TTAGGG and CCCTAA molecules non-invasively in 3 mummified Egyptian sisters from the 8th Century BC on exhibit at the Museo Egizio in Turin, Italy in order to estimate their approximate ages (at the time of death). The amounts of body telomere were 500 ng, 550 ng, and 750 ng. For the prehistoric Iceman (about 3350 B.C. to 3310 B.C) discovered in 1991 in the Italian Otzal Alps at about 3,200 meters altitude, estimated body telomere was about 400 ng and telomere in brain and heart was 1600 ng, similar to that of a contemporary human being. Although these studies are preliminary, the findings may have potential applications not only in anti-aging, cancer treatments, and pathophysiology of brain and heart, but also for the estimation of the difference in the ages of cadavers studied in archeology and forensic medicine.

Acupressure↗

PubMed2005

Extrachromosomal telomeric circles contribute to Rad52-, Rad50-, and polymerase delta-mediated telomere-telomere recombination in Saccharomyces cerevisiae.

Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the telomerase reverse transcriptase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. By using an in vivo inducible Cre-loxP system to generate and trace the fate of marked telomeric DNA-containing rings, the efficiency of telomere-telomere recombination can be determined quantitatively. We show that the telomeric loci are the primary sites at which a marked telomeric ring-containing DNA is observed among wild-type and surviving cells lacking telomerase. Marked telomeric DNAs can be transferred to telomeres and form tandem arrays through Rad52-, Rad50-, and polymerase delta-mediated recombination. Moreover, increases of extrachromosomal telomeric and Y' rings were observed in telomerase-deficient cells. These results imply that telomeres can use looped-out telomeric rings to promote telomere-telomere recombination in telomerase-deficient Saccharomyces cerevisiae.

DNA Polymerase III↗

PubMed1997

Telomere-telomere interactions and candidate telomere binding protein(s) in mammalian sperm cells.

We have used fluorescent in situ hybridization to localize telomeres within the nuclei of sperm from six mammals (human, rat, mouse, stallion, boar, and bull). In minimally swollen sperm of mouse and rat, most of the telomeres are clustered within a limited area in the posterior part of nuclei. In sperm of other species, telomeres associate into tetrameres and dimers. On swelling of sperm cells with heparin/dithiotriethol, telomere associations disperse, and hybridization signals become smaller in size and their numbers approach or correspond to the number of chromosome ends in a haploid genome. Quantitation of telomere loci indicates that dimeric associations are prominent features of mammalian sperm nuclear architecture. Higher order telomere-telomere interactions and organization develop during meiotic stages of human spermatogenesis. At this stage, telomeres also become associated with the nuclear membrane. In an attempt to elucidate the molecular mechanisms underlying telomere interactions in sperm, we have identified a novel protein activity that binds to the double-stranded telomeric repeat (TTAGGG)n. Sperm telomere binding protein(s) (STBP) was extracted from human and bull sperm by 0.5 M NaCl. STBP does not bind single-stranded telomeric DNA and is highly specific for single base substitutions in a duplex DNA sequence. Depending on the conditions of binding, we observed the formation of several nucleoprotein complexes. We have shown that there is a transition between complexes, which indicates that the slower migrating complex is a multimer of the higher mobility one. We propose that STBP participates in association between the telomere domains which were microscopically observed in mammalian spermatozoa.

Animals↗

PubMed1999

Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae.

Many Saccharomyces telomeres bear one or more copies of the repetitive Y' element followed by approximately 350 bp of telomerase-generated C(1-3)A/TG(1-3) repeats. Although most cells lacking a gene required for the telomerase pathway die after 50 to 100 cell divisions, survivors arise spontaneously in such cultures. These survivors have one of two distinct patterns of telomeric DNA (V. Lundblad and E. H. Blackburn, Cell 73:347-360, 1993). The more common of the two patterns, seen in type I survivors, is tandem amplification of Y' followed by very short tracts of C(1-3)A/TG(1-3) DNA. By determining the structure of singly tagged telomeres, chromosomes in type II survivors were shown to end in very long and heterogeneous-length tracts of C(1-3)A/TG(1-3) DNA, with some telomeres having 12 kb or more of C(1-3)A/TG(1-3) repeats. Maintenance of these long telomeres required the continuous presence of Rad52p. Whereas type I survivors often converted to the type II structure of telomeric DNA, the type II pattern was maintained for at least 250 cell divisions. However, during outgrowth, the structure of type II telomeres was dynamic, displaying gradual shortening as well as other structural changes that could be explained by continuous gene conversion events with other telomeres. Although most type II survivors had a growth rate similar to that of telomerase-proficient cells, their telomeres slowly returned to wild-type lengths when telomerase was reintroduced. The very long and heterogeneous-length telomeres characteristic of type II survivors in Saccharomyces are reminiscent of the telomeres in immortal human cell lines and tumors that maintain telomeric DNA in the absence of telomerase.

Chromosomes, Fungal↗

PubMed2003

Telomeric and interstitial telomeric sequences in holokinetic chromosomes of Lepidoptera: telomeric DNA mediates association between postpachytene bivalents in achiasmatic meiosis of females.

Telomeres, besides their main role in the protection and maintenance of chromosome ends, have several other vital functions in the cell cycle. We studied their role in the achiasmatic meiosis of female Lepidoptera, insects with holokinetic chromosomes. By fluorescence in-situ hybridization (FISH) with the insect telomeric probe, (TTAGG)n, we mapped the distribution of telomeric and interstitial telomeric sequences (ITS) in female meiotic chromosomes of two species, Orgyia antiqua with a reduced chromosome number (2n = 28) and Ephestia kuehniella mutants, possessing a radiation-induced chromosome fusion in the genome (2n = 59). In addition to the strong typical telomeric signals, O. antiqua displayed weaker hybridization signals in interstitial sites of pachytene bivalents. The observed ITS most probably reflect remnants of chromosomal rearrangements and support the hypothesis that the Orgyia karyotype had arisen by multiple fusions of ancestral chromosomes. On the other hand, the absence of ITS in the chromosome fusion of Ephestia indicated the loss of telomeres before the two original chromosomes fused. When the telomeric probe was amplified by enzymatic reaction with tyramid, the number of ITS observed increased in Orgyia, and a few ITS were also observed in several chromosomes of Ephestia but not in the fused chromosome. This suggests that the genomes of both species also contain ITS other than those originating from chromosome fusions. The analysis of female meiotic prophase I revealed non-homologous associations of postpachytene bivalents mediated by telomeric DNA, which were not observed in the pachytene stage. Surprisingly, in early postpachytene nuclei the telomeric associations also involved ITS, whereas later postpachytene nuclei displayed chains of bivalents interconnected only by true telomeres. This finding favours a hypothesis that telomeric associations between bivalents play a role in chromosome segregation in the achiasmatic meiosis of female Lepidoptera.

Animals↗

PubMed1995

Extra telomeres, but not internal tracts of telomeric DNA, reduce transcriptional repression at Saccharomyces telomeres.

Yeast telomeric DNA is assembled into a nonnucleosomal chromatin structure known as the telosome, which is thought to influence the transcriptional repression of genes placed in its vicinity, a phenomenon called telomere position effect (TPE). The product of the RAP1 gene, Rap1p, is a component of the telosome. We show that the fraction of cells exhibiting TPE can be substantially reduced by expressing large amounts of a deletion derivative of Rap1p that is unable to bind DNA, called Rap1 delta BBp, or by introducing extra telomeres on a linear plasmid, presumably because both compete in trans with telomeric chromatin for factor(s) important for TPE. This reduction in TPE, observed in three different strains, was demonstrated for two different genes, each assayed at a different telomere. In contrast, the addition of internal tracts of telomeric DNA on a circular plasmid had very little effect on TPE. The product of the SIR3 gene, Sir3p, appears to be limiting for TPE. Overexpression of Sir3p completely suppressed the reduction in TPE observed with expression of Rap1 delta BBp, but did not restore high levels of TPE to cells with extra telomeres. These results suggest that extra telomeres must titrate a factor other than Sir3p that is important for TPE. These results also provide evidence for a terminus-specific binding factor that is a factor with a higher affinity for DNA termini than for nonterminal tracts of telomeric DNA and indicate that this factor is important for TPE.

DNA, Fungal↗

PubMed2006

Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance.

Telomerase is a ribonucleoprotein complex that maintains the stability of chromosome ends and regulates replicative potential. Telomerase is upregulated in over 85% of human tumors, but not in adjacent normal tissues and represents a promising target for anticancer therapy. Most telomerase-based therapies rely on the inhibition of telomerase activity and require extensive telomere shortening before inducing any antiproliferative effect. Disturbances of telomere structure rather than length may be more effective in inducing cell death. Telomerase RNA subunits (hTRs) with mutations in the template region reconstitute active holoenzymes that incorporate mutated telomeric sequences. Here, we analysed the feasibility of an anticancer approach based on the combination of telomere destabilization and conventional chemotherapeutic drugs. We show that a mutant template hTR dictates the synthesis of mutated telomeric repeats in telomerase-positive cancer cells, without significantly affecting their viability and proliferative ability. Nevertheless, the mutant hTR increased sensitivity to anticancer drugs in cells with different initial telomere lengths and mechanisms of telomere maintenance and without requiring overall telomere shortening. This report is the first to show that interfering with telomere structure maintenance in a telomerase-dependent manner may be used to increase the susceptibility of tumor cells to anticancer drugs and may lead to the development of a general therapy for the treatment of human cancers.

Antineoplastic Agents↗

PubMed2004

HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila.

HP1 is a conserved chromosomal protein, first discovered in Drosophila, which is predominantly associated with the heterochromatin of many organisms. Recently, it has been shown that HP1 is required for telomere capping, telomere elongation, and transcriptional repression of telomeric sequences. Several studies have suggested a model for heterochromatin formation and epigenetic gene silencing in different species that is based on interactions among histone methyltransferases (HMTases), histone H3 methylated at lysine 9 (H3-MeK9), and the HP1 chromodomain. This model has been extended to HP1 telomeric localization by data showing that H3-MeK9 is present at all of the telomeres. Here, we tested this model, and we found that the capping function of HP1 is due to its direct binding to telomeric DNA, while the silencing of telomeric sequences and telomere elongation is due to its interaction with H3-MeK9.

Animals↗

PubMed1998

Characterisation of Leishmania telomeres reveals unusual telomeric repeats and conserved telomere-associated sequence.

Characterisation of the telomeres of Leishmania is important for understanding many aspects of the parasitic life of this primitive protozoan and for the completion of the physical map and sequencing of the genome. After sequencing more than 300 telomere-derived clones from Leishmania braziliensis and Leishmania major, a conserved 100 bp sequence was identified immediately adjacent to the telomere at the chromosome end and was named LCTAS (Leishmania conserved telomere-associated sequence). The LCTAS contains two conserved sequence boxes, and is present in all Leishmania species studied. The organisation of the LCTAS in the telomeric region differs between L. braziliensis and L. major: in L. major the LCTASs are tandemly repeated, while in L. braziliensis the LCTAS is present as a single copy per end. Two additional TASs with 1.6 kb and 274 bp repeat structures, which are apparently different to LCTAS, were isolated and mapped onto a L. braziliensis 250 kb multicopy minichromosome and the L. major chromosome 1, respectively. An unusual feature in L. braziliensis is that the telomeric repeats are often comprised of a novel tandem repeat CCCTAACCCGTGGA. A 'slippage' mechanism for LCTAS formation is proposed in this study as an alternative way for the synthesis and maintenance of telomeres and subtelomere regions.

Animals↗

PubMed1996

Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase.

Deletion of the telomerase RNA gene (TER1) in the yeast Kluyveromyces lactis results in gradual loss of telomeric repeats and progressively declining cell growth capability (growth senescence). We show that this initial growth senescence is characterized by abnormally large, defectively dividing cells and is delayed when cells initially contain elongated telomeres. However, cells that survive the initial catastrophic senescence emerge relatively frequently, and their subsequent growth without telomerase is surprisingly efficient. Survivors have lengthened telomeres, often much longer than wild type, but that are still subject to gradual shortening. Production of these postsenescence survivors is strongly dependent on the RAD52 gene. We propose that shortened, terminal telomeric repeat tracts become uncapped, promoting recombinational repair between them to regenerate lengthened telomeres in survivors. This process, which we term telomere cap-prevented recombination (CPR) may be a general alternative telomere maintenance pathway in eukaryotes.

DNA, Fungal↗

PubMed1990

Telomere-telomere recombination provides an express pathway for telomere acquisition.

DNA termini from Tetrahymena and Oxytricha, which bear C4A2 and C4A4 repeats respectively, can support telomere formation in Saccharomyces cerevisiae by serving as substrates for the addition of yeast telomeric C1-3A repeats. Previously, we showed that linear plasmids with 108 base pairs of C4A4 DNA (YLp108CA) efficiently acquired telomeres, whereas plasmids containing 28-64 base pairs of C4A4 DNA also promoted telomere formation, but with reduced efficiency. Although many of the C4A4 termini on these plasmids underwent recombination with a C4A2 terminus, the mechanism of telomere-telomere recombination was not established. We now report the sequence of the C4A4 ends from the linear plasmids. The results provide strong evidence for a novel recombination process involving a gene conversion event that requires little homology, occurs at or near the boundary of telomeric and nontelomeric DNA, and resembles the recombination process involved in bacteriophage T4 DNA replication.

Animals↗

PubMed2005

Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.

Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.

Animals↗

PubMed1994

RAP1 stimulates single- to double-strand association of yeast telomeric DNA: implications for telomere-telomere interactions.

Repressor Activator Protein 1 (RAP1) of Saccharomyces cerevisiae is an abundant nuclear protein implicated in telomere length maintenance, transactivation, and in the establishment of silent chromatin domains. The RAP1 binding site 5' of the yeast HIS4 gene is also a region of hyperrecombination in meiosis. We report here that as RAP1 binds its recognition consensus, it appears to untwist double-stranded DNA, which we detect as the introduction of a negative supercoil in circularization assays. Coincident with the RAP1-dependent untwisting, we observe stimulation of the association of a single-stranded yeast telomeric sequence with its homologous double-stranded sequence in a supercoiled plasmid. This unusual distortion of the DNA double helix by RAP1 may contribute to the RAP1-dependent enhancement of recombination rates and promote non-duplex strand interactions at telomeres.

Base Sequence↗

PubMed2006

Telomeres, interstitial telomeric repeat sequences, and chromosomal aberrations.

Telomeres are specialized nucleoproteic complexes localized at the physical ends of linear eukaryotic chromosomes that maintain their stability and integrity. The DNA component of telomeres is characterized by being a G-rich double stranded DNA composed by short fragments tandemly repeated with different sequences depending on the species considered. At the chromosome level, telomeres or, more properly, telomeric repeats--the DNA component of telomeres--can be detected either by using the fluorescence in situ hybridization (FISH) technique with a DNA or a peptide nucleic acid (PNA) (pan)telomeric probe, i.e., which identifies simultaneously all of the telomeres in a metaphase cell, or by the primed in situ labeling (PRINS) reaction using an oligonucleotide primer complementary to the telomeric DNA repeated sequence. Using these techniques, incomplete chromosome elements, acentric fragments, amplification and translocation of telomeric repeat sequences, telomeric associations and telomeric fusions can be identified. In addition, chromosome orientation (CO)-FISH allows to discriminate between the different types of telomeric fusions, namely telomere-telomere and telomere-DNA double strand break fusions and to detect recombination events at the telomere, i.e., telomeric sister-chromatid exchanges (T-SCE). In this review, we summarize our current knowledge of chromosomal aberrations involving telomeres and interstitial telomeric repeat sequences and their induction by physical and chemical mutagens. Since all of the studies on the induction of these types of aberrations were conducted in mammalian cells, the review will be focused on the chromosomal aberrations involving the TTAGGG sequence, i.e., the telomeric repeat sequence that "caps" the chromosomes of all vertebrate species.

Animals↗

PubMed2000

The function of DNA polymerase alpha at telomeric G tails is important for telomere homeostasis.

Telomere length control is influenced by several factors, including telomerase, the components of telomeric chromatin structure, and the conventional replication machinery. Although known components of the replication machinery can influence telomere length equilibrium, little is known about why mutations in certain replication proteins cause dramatic telomere lengthening. To investigate the cause of telomere elongation in cdc17/pol1 (DNA polymerase alpha) mutants, we examined telomeric chromatin, as measured by its ability to repress transcription on telomere-proximal genes, and telomeric DNA end structures in pol1-17 mutants. pol1-17 mutants with elongated telomeres show a dramatic loss of the repression of telomere-proximal genes, or telomeric silencing. In addition, cdc17/pol1 mutants grown under telomere-elongating conditions exhibit significant increases in single-stranded character in telomeric DNA but not at internal sequences. The single strandedness is manifested as a terminal extension of the G-rich strand (G tails) that can occur independently of telomerase, suggesting that cdc17/pol1 mutants exhibit defects in telomeric lagging-strand synthesis. Interestingly, the loss of telomeric silencing and the increase in the sizes of the G tails at the telomeres temporally coincide and occur before any detectable telomere lengthening is observed. Moreover, the G tails observed in cdc17/pol1 mutants incubated at the semipermissive temperature appear only when the cells pass through S phase and are processed by the time cells reach G(1). These results suggest that lagging-strand synthesis is coordinated with telomerase-mediated telomere maintenance to ensure proper telomere length control.

Base Sequence↗

PubMed2001

spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast.

Telomeres are essential for genome integrity. scRap1 (S. cerevisiae Rap1) directly binds to telomeric DNA and regulates telomere length and telomere position effect (TPE) by recruiting two different groups of proteins to its RCT (Rap1 C-terminal) domain. The first group, Rif1 and Rif2, regulates telomere length. The second group, Sir3 and Sir4, is involved in heterochromatin formation. On the other hand, human TRF1 and TRF2, as well as their fission yeast homolog, Taz1, directly bind to telomeric DNA and negatively regulate telomere length. Taz1 also plays important roles in TPE and meiosis. Human Rap1, the ortholog of scRap1, negatively regulates telomere length and appears to be recruited to telomeres by interacting with TRF2. Here, we describe two novel fission yeast proteins, spRap1 (S. pombe Rap1) and spRif1 (S. pombe Rif1), which are orthologous to scRap1 and scRif1, respectively. spRap1 and spRif1 are independently recruited to telomeres by interacting with Taz1. The rap1 mutant is severely defective in telomere length control, TPE, and telomere clustering toward the spindle pole body (SPB) at the premeiotic horsetail stage, indicating that spRap1 has critical roles in these telomere functions. The rif1 mutant also shows some defects in telomere length control and meiosis. Our results indicate that Taz1 provides binding sites for telomere regulators, spRap1 and spRif1, which perform the essential telomere functions. This study establishes the similarity of telomere organization in fission yeast and humans.

Amino Acid Sequence↗

PubMed2002

Involvement of replicative polymerases, Tel1p, Mec1p, Cdc13p, and the Ku complex in telomere-telomere recombination.

Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of the reverse transcriptase telomerase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Genetic studies have led to the identification of DNA polymerases, cell cycle checkpoint proteins, and telomere binding proteins involved in the telomerase pathway. However, how these proteins affect telomere-telomere recombination has not been identified to date. Using an assay to trace the in vivo recombinational products throughout the course of survivor development, we show here that three major replicative polymerases, alpha, delta, and epsilon, play roles in telomere-telomere recombination and that each causes different effects and phenotypes when they as well as the telomerase are defective. Polymerase delta appears to be the main activity for telomere extension, since neither type I nor type II survivors arising via telomere-telomere recombination were seen in its absence. The frequency of type I versus type II is altered in the polymerase alpha and epsilon mutants relative to the wild type. Each prefers to develop a particular type of survivor. Moreover, type II recombination is mediated by the cell cycle checkpoint proteins Tel1 and Mec1, and telomere-telomere recombination is regulated by telomere binding protein Cdc13 and the Ku complex. Together, our results suggest that coordination between DNA replication machinery, DNA damage signaling, DNA recombination machinery, and the telomere protein-DNA complex allows telomere recombination to repair telomeric ends in the absence of telomerase.

Antigens, Nuclear↗