The Telomere and Telomerase: How do they Interact?

Blackburn, Elizabeth H.; Bhattacharyya, Anamitra; Gilley, David; Kirk, Karen E.; Krauskopf, Anat; McEachern, Michael J.; Prescott, J; Ware, Tracy L.

doi:10.1002/9780470515433.ch2

Cited by 14 publications

(11 citation statements)

References 39 publications

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“…While quadruplex DNA continued to be studied over the subsequent decades (2), the structure was regarded as a biophysical oddity, with little functional relevance. That situation changed when G-rich sequences capable of forming G-quadrplexes were found to be highly conserved in telomeres (3,4). The finding that G-quadruplexes prevented replication of telomeric DNA by telomerase (5) suggested a new strategy for chemotherapy (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Use of competition dialysis in the discovery of G-quadruplex selective ligands

Ragazzon

Chaires

2007

Methods

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G-quadrplex DNA can exist in a rich variety of structural forms, ranging from unimolecular folded structures containing diverse types of loops and strand oreintations, to bimolecular dimeric structures, and finally to tetramolecular parallel-stranded structures. These diverse structures present numerous potential small molecule binding sites with distinctive properties. There is mounting evidence for important functional roles for G-quadruplex structures in biology. G-quadruplexes may participate in the maintainance of telomeres, in transcriptional regulation and, in mRNA, may act to modulate translation. G-quadruplexes thus represent an attractive target for new small-molecule therapeutic agents. Competition dialysis provides a useful tool for the discovery of small molecules that selectively recognize the unique structural features of G-quadruplexes. The principles and practice of the competition dialysis experiment are described here.

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Section: Introductionmentioning

confidence: 99%

Use of competition dialysis in the discovery of G-quadruplex selective ligands

Ragazzon

Chaires

2007

Methods

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“…Ribonucleoproteins (RNPs), a large and diverse group of macromolecular complexes composed of both RNA and protein components, are involved in numerous cellular processes (e.g., Greider and Blackburn 1987;Green and Noller 1997;Blackburn 1999;Ramakrishnan 2002;Doudna and Batey 2004;Meister and Tuschl 2004;Meier 2005). In light of the ubiquity and diversity of RNPs, a key challenge is to understand how functions arise from the synergistic interaction of RNA and protein components.…”

Section: Introductionmentioning

confidence: 99%

Probing the architecture of the B. subtilis RNase P holoenzyme active site by cross-linking and affinity cleavage

Niranjanakumari¹,

Day-Storms²,

Ahmed³

et al. 2007

RNA

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Bacterial ribonuclease P (RNase P) is a ribonucleoprotein complex composed of one catalytic RNA (PRNA) and one protein subunit (P protein) that together catalyze the 59 maturation of precursor tRNA. High-resolution X-ray crystal structures of the individual P protein and PRNA components from several species have been determined, and structural models of the RNase P holoenzyme have been proposed. However, holoenzyme models have been limited by a lack of distance constraints between P protein and PRNA in the holoenzyme-substrate complex. Here, we report the results of extensive cross-linking and affinity cleavage experiments using single-cysteine P protein variants derivatized with either azidophenacyl bromide or 5-iodoacetamido-1,10-o-phenanthroline to determine distance constraints and to model the Bacillus subtilis holoenzyme-substrate complex. These data indicate that the evolutionarily conserved RNR motif of P protein is located near (<15 Å ) the pre-tRNA cleavage site, the base of the pre-tRNA acceptor stem and helix P4 of PRNA, the putative active site of the enzyme. In addition, the metal binding loop and N-terminal region of the P protein are proximal to the P3 stem-loop of PRNA. Studies using heterologous holoenzymes composed of covalently modified B. subtilis P protein and Escherichia coli M1 RNA indicate that P protein binds similarly to both RNAs. Together, these data indicate that P protein is positioned close to the RNase P active site and may play a role in organizing the RNase P active site.

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“…Telomere shortening during cell division can be attenuated by the activity of telomerase, a unique reverse transcriptase that adds TTAGGG repeats to telomeres upon DNA synthesis (Blackburn, 1999;McEachern et al, 2000). In human somatic cells telomerase is inactive.…”

Section: Discussionmentioning

confidence: 99%

“…Telomeres are non-coding DNA sequences that cap the ends of chromosomes and protect against deletions, end-to-end fusion and recombination of the DNA (Blackburn, 1999). In humans, telomeric DNA consists of (TTAGGG)n repeats forming stretches of 3-12 kb in length.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress causes telomere damage in Fanconi anaemia cells – a possible predisposition for malignant transformation

et al. 2008

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SummaryFanconi anaemia (FA) is an autosomal recessive and X‐linked disease characterized by severe genetic instability and increased incidence of cancer. One explanation for this instability may be the cellular hypersensitivity to oxidative stress leading to chromosomal breaks. This study explored the possible oxidative damage to telomeres of FA lymphocyte cell line, HSC536/N, and its possible effect on telomere function. We postulated that combination of oxidative damage with overexpression of telomerase may provide a possible model for malignant transformation in FA. The cells were grown in the presence of telomerase inhibitor and exposed for 1 month to H2O2 combined with various antioxidants. This exposure caused shortening of telomere length and damage to the telomere single stranded overhang, which was prevented by several oxidants. This shortening was associated with development of severe telomere dysfunction. Control cells did not exhibit this sensitivity to H2O2. Telomere dysfunction did not evoke damage response in FA cells, in contrast to normal P53 upregulation in control cells. Reconstitution of telomerase activity protected FA telomeres from further oxidative damage. These results suggest a scenario in which oxidative stress causes telomere shortening and ensuing telomere dysfunction may form the basis for malignant transformation in FA cells. Upregulation of telomerase activity in sporadic FA cells may perpetuate that process, thus explaining the malignant character of FA cells in vivo.

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The Telomere and Telomerase: How do they Interact?

Cited by 14 publications

References 39 publications

Use of competition dialysis in the discovery of G-quadruplex selective ligands

Use of competition dialysis in the discovery of G-quadruplex selective ligands

Probing the architecture of the B. subtilis RNase P holoenzyme active site by cross-linking and affinity cleavage

Oxidative stress causes telomere damage in Fanconi anaemia cells – a possible predisposition for malignant transformation

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