The <i>Caenorhabditis elegans</i> Rad17 Homolog HPR-17 Is Required for Telomere Replication

Boerckel, Julie; Walker, Dana; Ahmed, Shawn

doi:10.1534/genetics.106.070201

Cited by 21 publications

(30 citation statements)

References 52 publications

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“…In addition, the sterility phenotypes of mrt-2 and hpr-17 have been addressed in detail and are fully consistent with resulting from telomerase-dependent telomere repeat addition defects (22,23,28). Note that although mrt-2 is required for telomerase-mediated telomere repeat addition in vivo (22), trt-1 is wild type in mrt-2 strains, and we cannot exclude the possibility that mutation of pot-2 allows for infrequent stochastic Fig.…”

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

confidence: 65%

“…The functional significance of the DNA damage response proteins in ALT remains unclear and, in mammals, is difficult to determine because the 9-1-1 complex is essential for cell viability (27). Deficiencies for the C. elegans 9-1-1 complex subunits, MRT-2 and HUS-1, and the clamp loader HPR-17, result in viable strains that are defective for telomerasemediated telomere repeat addition in vivo (23,28,29). These mutants can survive for many generations before becoming sterile as a consequence of critical telomere shortening and endto-end chromosome fusion.…”

Section: Survivors Of Telomerase Deficiency In C Elegans Can Have Nomentioning

confidence: 99%

“…3B; n = 100 strains each). Given that the telomeres of mrt-2, hpr-17, and trt-1 single mutants erode at similar rates to those of trt-1; mrt-2 and trt-1; hpr-17 double mutants (22,28), the lack of survivors for mrt-2 and hpr-17 suggests that the 9-1-1 complex is required for ALT in C. elegans.…”

Section: Survivors Of Telomerase Deficiency In C Elegans Can Have Nomentioning

confidence: 99%

“…Dashed lines surround chromosomes of individual oocyte nuclei. Wild-type oocytes uniformly display six DAPI-positive spots, comparable to F (22,23,28 access of telomerase to telomeres, thereby promoting survival only where large numbers of worms were transferred. However, because pot-2; mrt-2 strains fail to survive when subjected to population bottlenecks, and because trt-1; pot-2 strains display properties in common with pot-2; mrt-2 strains, such as a high frequency of survival where large numbers of worms were transferred, and maintenance of predominantly normal telomere lengths (Fig.…”

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 Normalmentioning

confidence: 65%

Section: Survivors Of Telomerase Deficiency In C Elegans Can Have Nomentioning

confidence: 99%

Section: Survivors Of Telomerase Deficiency In C Elegans Can Have Nomentioning

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.

Self Cite

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“…The heterotrimeric 9-1-1 complex, composed of RAD9, RAD1 and HUS1, is phosphorylated by ATR and is needed for full ATR-activation in yeast and vertebrate systems. In C. elegans the corresponding mutants are defective in triggering DNA damage checkpoint responses upon IR treatment (Gartner et al 2000 ;Boulton et al 2002 ;Hofmann et al 2002 ;Boerckel et al 2007 ) . At the same time these genes are involved in telomere replication, possibly by being required for recruiting telomerase.…”

Section: Upstream Dna Damage Checkpoint Signalling In the C Elegans mentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Cancer models in Caenorhabditis elegans

Kirienko

Mani

Fay

2010

Developmental Dynamics

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Although now dogma, the idea that non-vertebrate organisms such as yeast, worms, and flies could inform, and in some cases even revolutionize, our understanding of oncogenesis in humans was not immediately obvious. Aided by the conservative nature of evolution and the persistence of a cohort of devoted researchers, the role of model organisms as a key tool in solving the cancer problem has, however, become widely accepted. In this review, we focus on the nematode Caenorhabditis elegans and its diverse and sometimes surprising contributions to our understanding of the tumorigenic process. Specifically, we discuss findings in the worm that address a well-defined set of processes known to be deregulated in cancer cells including cell cycle progression, growth factor signaling, terminal differentiation, apoptosis, the maintenance of genome stability, and developmental mechanisms relevant to invasion and metastasis.

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The Caenorhabditis elegans Rad17 Homolog HPR-17 Is Required for Telomere Replication

Cited by 21 publications

References 52 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

Germ Cell Apoptosis and DNA Damage Responses

Cancer models in Caenorhabditis elegans

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