C. elegans Telomeres Contain G-Strand and C-Strand Overhangs that Are Bound by Distinct Proteins

Raı́ces, Marcela; Verdún, Ramiro E.; Compton, Sarah A.; Haggblom, Candy; Griffith, Jack D.; Dillin, Andrew; Karlseder, Jan

doi:10.1016/j.cell.2007.12.039

Cited by 126 publications

(176 citation statements)

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“…Of two C. elegans POT1-related genes that exhibit elongated telomeres when absent, pot-1 and pot-2 (24, 32), we show that deficiency for pot-2 specifically promotes the frequency of survival via ALT, whereas deficiency for pot-1 results in ALT strains that possess fewer chromosome fusions. These results agree with a previous report suggesting that pot-1 and pot-2 have overlapping but distinct biological functions (32). The high frequency of trt-1; pot-2 survivors is consistent with a role for the POT-2 OB2 fold protein in binding and protecting the 3′ end of a chromosome (32), where ALT could initiate by engaging an illegitimate replication or recombination mechanism (Fig.…”

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalsupporting

confidence: 82%

“…Two additional POT1 genes, pot-1 (also known as CeOB2) and pot-2 (also known as CeOB1), which encode OB1 and OB2 folds, respectively, have been shown to display elongated telomeres when mutated (24,32). Moreover, pot-1 mutants possess heterogeneous telomeres similar to those observed in human ALT cells (32). To test the hypothesis that pot-1 may promote ALT, we constructed the double mutant strains trt-1; pot-1, trt-1; pot-2, and trt-1; pot-3 using well-outcrossed pot-1, pot-2, or pot-3 mutant backgrounds that possessed telomeres of wild-type lengths.…”

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

“…C. elegans MRT-1, a dual-domain protein comprised of an OB2 fold fused to an interstrand cross-link repair domain, is required for telomerase-mediated telomere repeat addition in vivo (31), whereas worms lacking POT-3, which also harbors an OB2 fold, exhibit wild-type telomeres (32). Two additional POT1 genes, pot-1 (also known as CeOB2) and pot-2 (also known as CeOB1), which encode OB1 and OB2 folds, respectively, have been shown to display elongated telomeres when mutated (24,32). Moreover, pot-1 mutants possess heterogeneous telomeres similar to those observed in human ALT cells (32).…”

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

“…The C. elegans genome harbors four genes that encode homologs of mammalian Protection Of Telomeres 1 (POT1), a protein that binds single-stranded telomeric DNA via two oligosaccharide/oligonucleotide (OB) folds, OB1 and OB2 (30)(31)(32). C. elegans MRT-1, a dual-domain protein comprised of an OB2 fold fused to an interstrand cross-link repair domain, is required for telomerase-mediated telomere repeat addition in vivo (31), whereas worms lacking POT-3, which also harbors an OB2 fold, exhibit wild-type telomeres (32). Two additional POT1 genes, pot-1 (also known as CeOB2) and pot-2 (also known as CeOB1), which encode OB1 and OB2 folds, respectively, have been shown to display elongated telomeres when mutated (24,32).…”

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

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Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

Cheng¹,

Shtessel

Brady

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Canonical telomere repeats at chromosome termini can be maintained by a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Human cancers that survive via ALT can exhibit long and heterogeneous telomeres, although many telomerase-negative tumors possess telomeres of normal length. Here, we report that Caenorhabditis elegans telomerase mutants that survived via ALT possessed either long or normal telomere lengths. Most ALT strains displayed end-to-end chromosome fusions, suggesting that critical telomere shortening occurred before or concomitant with ALT. ALT required the 9-1-1 DNA damage response complex and its clamp loader, HPR-17. Deficiency for the POT-2 telomere binding protein promoted ALT in telomerase mutants, overcame the requirement for the 9-1-1 complex in ALT, and promoted ALT with normal telomere lengths. We propose that telomerase-deficient human tumors with normal telomere lengths could represent a mode of ALT that is facilitated by telomere capping protein dysfunction. PROTECTION OF TELOMERES-2 | telomere maintenanceT elomeres are tandem repeat tracts that cap the ends of linear chromosomes and erode with each cell cycle because of the inability of canonical DNA polymerases to completely replicate chromosome termini (1). However, the ribonucleoprotein telomerase combats this erosion by adding de novo telomeric repeats via reverse transcription (2). Progressive telomere shortening during proliferation of human somatic cells can trigger senescence, which serves as a major tumor suppression mechanism (3). Bypass of senescence and further cell proliferation leads to critical telomere shortening and crisis, resulting in high levels of cell death due to chromosome instability (4). Many tumors overcome this proliferation barrier by activating expression of the telomerase reverse transcriptase. The remaining 10-15% of human tumors do not possess telomerase activity (5, 6).S. cerevisiae strains deficient for telomerase can survive with long and heterogeneous telomeres composed of amplified telomere repeats (type II survivors) (7,8). Analogous to type II survivors, long and heterogeneous telomeres occur in almost all in vitro immortalized cell lines and tumor-derived cells lines that are telomerase-negative (9-11). Furthermore, extensive analysis of telomerase activity and telomere length from primary human tumor samples has revealed that certain telomerase-negative tumors possess long and heterogeneous telomeres, defined as alternative lengthening of telomeres (ALT) tumors (9). However, the majority (81/108) of primary tumors lacking telomerase activity have telomeres of normal lengths (9,(12)(13)(14)(15). This subset of telomerase-negative tumors may have become neoplastic before exhausting their telomere repeat reserves (9, 16). Alternatively, these tumors could have evolved via the same telomeredriven crisis events that give rise to ALT tumors, followed by activation of a distinct form of ALT that maintains telomeres of apparently normal lengths (9).Homologous recombinatio...

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Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalsupporting

confidence: 82%

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

Section: Pot-2 Represses a Distinct Form Of Alt With Telomeres Of Normalmentioning

confidence: 99%

See 2 more Smart Citations

Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

Cheng¹,

Shtessel

Brady

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…However, notable exceptions do exist. The roundworm Caenorhabditis elegans contains both 3 0 G-overhangs as well as 5 0 C-overhangs (Raices et al 2008). Several genera of insects and plants do contain long DNA repeats (Martinez et al 2001).…”

Section: H Erman Muller and Barbara Mcclintockmentioning

confidence: 99%

Replication of Telomeres and the Regulation of Telomerase

Pfeiffer

Lingner

2013

Cold Spring Harbor Perspectives in Biology

112

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Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span. In this review, we introduce the current knowledge on telomere composition and structure. We then discuss in depth the current understanding of how telomere components mediate their function during semiconservative DNA replication and how telomerase is regulated at the end of the chromosome. We focus our discussion on the telomeres from mammals and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe.

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Paradoxical delay of senescence upon depletion of BRCA2 in telomerase‐deficient worms

et al. 2016

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BRCA 2 is a multifunctional tumor suppressor involved in homologous recombination ( HR ), mitotic checkpoint regulation, and telomere homeostasis. Absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that BRCA 2 has positive and negative effects on telomere length regulation along the path to tumorigenesis. Using Caenorhabditis elegans as a model, we show here that depletion of BRC ‐2, an ortholog of BRCA 2, paradoxically delays senescence in telomerase‐deficient mutant worms. Telomerase‐deficient worms ( trt‐1 ) exhibit early replication senescence due to short telomeres. It should be noted that worms mutated in brc‐2 are not viable as well due to massive genotoxic insults. However, when BRC ‐2 is depleted by RNA interference in trt‐1 mutant worms, the number of generations is unexpectedly increased with telomere length maintained, compared to telomerase mutants. Interestingly, depletion of other HR genes such as rad‐51 and rad‐54 exhibited similar effects. In worms doubly deficient of telomerase and brc‐2 , rad‐51 , or rad‐54 , extra telomeric C‐circles were generated, suggesting that abrogation of HR induces an alteration in telomere environment favorable to illegitimate telomere maintenance when telomerase is absent. Collectively, absence of BRC ‐2 in telomerase‐deficient background first leads to telomere shortening, followed by an induction of an as‐yet‐unknown telomere maintenance pathway, resulting in delay of senescence. The results have implications in the understanding of dysfunctional BRCA 2‐associated tumorigenesis.

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C. elegans Telomeres Contain G-Strand and C-Strand Overhangs that Are Bound by Distinct Proteins

Cited by 126 publications

References 53 publications

Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths

Replication of Telomeres and the Regulation of Telomerase

Paradoxical delay of senescence upon depletion of BRCA2 in telomerase‐deficient worms

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