C. elegans clk-2, a gene that limits life span, encodes a telomere length regulator similar to yeast telomere binding protein Tel2p

Lim, Chang-Su; Mian, I. Saira; Dernburg, Abby F.; Campisi, Judith

doi:10.1016/s0960-9822(01)00526-7

Cited by 50 publications

(31 citation statements)

References 24 publications

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“…Of the C. elegans genes identified so far whose mutations make worms live longer, only one gene, clk-2, was reported to affect telomere length, with some controversy [20][21][22] . It would be difficult to determine whether long telomeres extend lifespan in these worms, because the clk-2 mutation causes many other pleiotropic effects, such as a defective DNA checkpoint function and slow metabolism 23 that induces stress resistance in the soma.…”

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confidence: 99%

Long lifespan in worms with long telomeric DNA

et al. 2004

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Telomere length is a crucial factor in senescence 1-3 , but it has not been determined whether animals with long telomeres live longer than those with normal-length telomeres in the isogenic background of a given species. Here we show the effect of long telomeres on lifespan in the nematode Caenorhabditis elegans. We examined the effect of telomere length on lifespan by overexpressing HRP-1, a telomere-binding protein, which gradually increased telomere length in worms. Worms with longer telomeres lived longer. We confirmed that the extension of lifespan was due to the increased telomere length, and not to the overexpression of HRP-1 per se, by examining the lifespans of nontransgenic progeny of the transgenic worms, who retained the longer telomeres. The lifespan-extending effect of long telomeres was dependent on daf-16. The number of germ stem cells was not affected in worms with long telomeres, indicating that the telomere effect on lifespan is independent of germ stem cell cycling. Worms with long telomeres were more resistant to heat stress. Taken together, our results suggest that signaling may be initiated in postmitotic somatic cells by telomere length to regulate organismal lifespan.

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Long lifespan in worms with long telomeric DNA

et al. 2004

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“…On the other hand, S. pombe Tel2 apparently does not play a critical role in telomere length control, because Tel2 repression did not show any changes in telomere length (data not shown). In C. elegans, rad-5 and clk-2 mutations have little effect on telomere length (41), whereas other reports argued that clear changes in telomere length (both longer and shorter) are observed in clk-2 mutants (42,43). In humans, overexpression of CLK2 gradually lengthens telomere DNA (45), but the effect of inactivation of CLK2 on telomere length is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In Caenorhabditis elegans, the rad-5 mutant was isolated as a radiationsensitive mutant showing high sensitivity to UV and x-ray irradiation (38), and the clk-2 mutant was isolated as a viable maternal-effect mutant showing alteration of the timing of some developmental and behavioral events, including the embryonic cell cycle and life span (39,40). Ahmed et al (41) showed that rad-5 is allelic to clk-2, and cloning of the rad-5/ clk-2 gene revealed that it encodes a protein homologous to S. cerevisiae Tel2 (42,43). The rad-5/clk-2 mutant is also sensitive to HU treatment and is defective in the DNA replication checkpoint (41).…”

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Tel2 Is Required for Activation of the Mrc1-mediated Replication Checkpoint

Shikata

Ishikawa²,

Kanoh

2007

Journal of Biological Chemistry

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Proteins belonging to the Tel2/Rad-5/Clk-2 family are conserved among eukaryotes and are involved in various cellular processes, such as cell proliferation, telomere maintenance, the biological clock, and the DNA damage checkpoint. However, the molecular mechanisms underlying the functions of these molecules remain largely unclear. Here we report that in the fission yeast, Schizosaccharomyces pombe, Tel2 is required for efficient phosphorylation of Mrc1, a mediator of DNA replication checkpoint signaling, and for activation of Cds1, a replication checkpoint kinase, when DNA replication is blocked by hydroxyurea. In fact, Tel2 is required for survival of replication fork arrest and for the replication checkpoint in cells lacking Chk1, another checkpoint kinase the role of which overlaps that of Cds1 in cell cycle arrest by replication block. In addition, Tel2 plays important roles in entry into S phase and in genome stability. Tel2 is essential for vegetative cell growth, and the tel2⌬ strain accumulated cells with 1C DNA content after germination. In the absence of hydroxyurea, Tel2 is vital in the mutant lacking Swi1, a component of the replication fork protection complex, and multiple Rad22 DNA repair foci were frequently observed in Tel2-repressed swi1⌬ cells especially at S phase. In contrast, the cds1⌬swi1⌬ mutant did not show such lethality. These results indicate that S. pombe Tel2 plays important roles in the Mrc1-mediated replication checkpoint as well as in the Cds1-independent regulation of genome integrity.

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“…For example, S. cerevisiae Tel2p works in the same telomere maintenance pathway as Tel1p (Runge and Zakian 1996) and seems to bind to telomeric DNA (Kota and Runge 1998). Although a role of Tel2p in the DDR has not yet been described, its human counterpart controls sensitivity to DNA damaging agents whereas its C. elegans ortholog influences telomere length, the S-phase checkpoint, and controls life span and biological rhythms (Ahmed et al 2001;Benard et al 2001;Lim et al 2001;Jiang et al 2003).…”

Section: Dna-damage Checkpoint Proteins and Telomeresmentioning

confidence: 99%

Functional links between telomeres and proteins of the DNA-damage response

Fagagna¹,

Teo²,

Jackson³

2004

Genes Dev.

254

191

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In response to DNA damage, cells engage a complex set of events that together comprise the DNA-damage response (DDR). These events bring about the repair of the damage and also slow down or halt cell cycle progression until the damage has been removed. In stark contrast, the ends of linear chromosomes, telomeres, are generally not perceived as DNA damage by the cell even though they terminate the DNA double-helix. Nevertheless, it has become clear over the past few years that many proteins involved in the DDR, particularly those involved in responding to DNA double-strand breaks, also play key roles in telomere maintenance. In this review, we discuss the current knowledge of both the telomere and the DDR, and then propose an integrated model for the events associated with the metabolism of DNA ends in these two distinct physiological contexts.All organisms respond to interruptions in the DNA double-helix by promptly launching the DNA-damage response (DDR). This involves the mobilization of DNArepair factors and the activation of pathways, often termed checkpoint pathways, which temporarily or permanently delay cell cycle progression. Although the integrity of the DNA double-helix is perturbed by telomeres (the ends of linear chromosomes), these structures generally escape activating the DDR. Several explanations have been proposed to explain the exceptional nature of telomeres in this regard. Thus, it has been suggested that a telomere might not be recognized by components of the DDR because of its unique DNA sequence and structure, its specific localization within the cell nucleus, and/or because of the actions of specific proteins associated with it. Although this is partly correct, recent findings have revealed that, contrary to initial expectations, various proteins involved in the DDR physically associate with telomeres and actually play important roles in regulating normal telomeric functions. In this review, we focus on the role of DDR factors in regulating telomere length and stability, and also explain how dysfunctional telomeres can trigger the DDR. Before doing this, however, we first summarize the salient features of both telomeres and the DDR. Telomere structure and biologyThe ends of linear chromosomes contain long stretches of DNA tandem repeats (TTAGGG in vertebrates) and terminate in a 3Ј protruding single-stranded DNA overhang. Due to the inability of the standard lagging-strand DNA replication machinery to copy the most distal telomere sequences (i.e., those at the very end of the chromosome) and to the additional exonucleolytic processing needed to generate protruding overhangs at both ends, telomeric DNA progressively decreases in length as cells go through successive division cycles. Hence, in the absence of specialized telomere homeostatic mechanisms this would ultimately lead to the loss of all telomeric sequences and subsequently to the loss of more internal essential genetic information and ensuing cell death. To circumvent this, many cells maintain their telomeres by the action of telo...

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C. elegans clk-2, a gene that limits life span, encodes a telomere length regulator similar to yeast telomere binding protein Tel2p

Cited by 50 publications

References 24 publications

Long lifespan in worms with long telomeric DNA

Long lifespan in worms with long telomeric DNA

Tel2 Is Required for Activation of the Mrc1-mediated Replication Checkpoint

Functional links between telomeres and proteins of the DNA-damage response

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