Complex interactions between the DNA-damage response and mammalian telomeres

Arnoult, Nausica; Karlseder, Jan

doi:10.1038/nsmb.3092

Cited by 185 publications

(177 citation statements)

References 100 publications

(144 reference statements)

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“…Generally, telomeric DNA is composed of simple sequence repeats arranged as a tract of duplex repeats followed by a single-stranded 3Ј overhang (3). These telomeric repeats recruit sequence-specific double-stranded and single-stranded DNA-binding proteins to nucleate the assembly of telomere-specific protein complexes, which sequester chromosome termini from DNA damage sensors (3,4). The accessibility of strand termini is strictly regulated, and as a consequence, the 3Ј overhang has a fixed length range in any given species.…”

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confidence: 99%

Shared Subunits of Tetrahymena Telomerase Holoenzyme and Replication Protein A Have Different Functions in Different Cellular Complexes

Upton

Chan

Feigon

et al. 2017

Journal of Biological Chemistry

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Edited by Patrick SungIn most eukaryotes, telomere maintenance relies on telomeric repeat synthesis by a reverse transcriptase named telomerase. To synthesize telomeric repeats, the catalytic subunit telomerase reverse transcriptase (TERT) uses the RNA subunit (TER) as a template. In the ciliate Tetrahymena thermophila, the telomerase holoenzyme consists of TER, TERT, and eight additional proteins, including the telomeric repeat single-stranded Telomeres, which are the DNA-protein complexes at the ends of eukaryotic chromosomes, are essential for genome stability and long term cellular proliferation (1, 2). Generally, telomeric DNA is composed of simple sequence repeats arranged as a tract of duplex repeats followed by a single-stranded 3Ј overhang (3). These telomeric repeats recruit sequence-specific double-stranded and single-stranded DNA-binding proteins to nucleate the assembly of telomere-specific protein complexes, which sequester chromosome termini from DNA damage sensors (3, 4). The accessibility of strand termini is strictly regulated, and as a consequence, the 3Ј overhang has a fixed length range in any given species. This 3Ј overhang is critical for telomere end protection, but it must be created anew after genome replication in a manner that obliges a loss of telomeric repeats with each round of cell division (5). Single-celled organisms have a relatively short telomeric 3Ј overhang and consequently lose a few or tens of base pairs per cell division, whereas human cells have relatively long overhangs on the order of ϳ100 nucleotides (nt) 3 and correspondingly lose more base pairs of telomeric repeats per cell division (6, 7).To compensate for incomplete telomere replication by conventional DNA polymerases, most eukaryotes rely on the ribonucleoprotein (RNP) telomerase (8). Each telomeric repeat array is maintained in a dynamic equilibrium of attrition from genome replication and telomerase-mediated de novo synthesis. Telomerase acts by reverse transcribing the integral RNA component, TER, with the catalytic telomerase reverse transcriptase protein, TERT (9, 10). By copying a short template sequence within its RNA moiety, telomerase synthesizes the guanosine-rich telomeric DNA strand (G-strand) running 5Ј to 3Ј toward a chromosome terminus (e.g. repeats of TTGGGG in the ciliate Tetrahymena or TTAGGG in vertebrates). TERT and TER assembled in a heterologous cell extract can reconstitute repeat synthesis activity; therefore, an RNP with these two subunits is considered the minimal recombinant RNP (11,12). For biologically functional telomerase holoenzyme, TER and TERT require a number of other subunits to properly fold TER, assemble TER with TERT, and allow active RNP to elongate telomeres (13,14). Although telomerase holoenzyme sub-* The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The nucleotide sequence (s)

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confidence: 99%

Shared Subunits of Tetrahymena Telomerase Holoenzyme and Replication Protein A Have Different Functions in Different Cellular Complexes

Upton

Chan

Feigon

et al. 2017

Journal of Biological Chemistry

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“…Both function via interactions with another shelterin component TRF2 (Telomere repeat binding-factor 2). 33,34 Phenotypically, many of the features seen in LIG4/Dubowitz syndrome are also seen in DC patients with biallelic RTEL1 mutations ( Table 2). 7 This supports the idea that mutations in LIG4 can give rise to a phenotype that is reminiscent of DC as caused by a gene that has a known association with telomere biology.…”

Section: Discussionmentioning

confidence: 99%

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

et al. 2016

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“…The ends of linear eukaryotic chromosomes are organized into well-defined structures called telomeres (Doksani and de Lange 2014;Arnoult and Karlseder 2015). The telomeric DNA is looped back in a DNA structure called a T-loop that prevents the DNA end from being exposed (Griffith et al 1999;Doksani et al 2013).…”

Section: Ufbs At Telomeresmentioning

confidence: 99%

Knotty Problems during Mitosis: Mechanistic Insight into the Processing of Ultrafine DNA Bridges in Anaphase

Sarlós

Biebricher

Petermann

et al. 2017

Cold Spring Harb Symp Quant Biol

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To survive and proliferate, cells have to faithfully segregate their newly replicated genomic DNA to the two daughter cells. However, the sister chromatids of mitotic chromosomes are frequently interlinked by so-called ultrafine DNA bridges (UFBs) that are visible in the anaphase of mitosis. UFBs can only be detected by the proteins bound to them and not by staining with conventional DNA dyes. These DNA bridges are presumed to represent entangled sister chromatids and hence pose a threat to faithful segregation. A failure to accurately unlink UFB DNA results in chromosome segregation errors and binucleation. This, in turn, compromises genome integrity, which is a hallmark of cancer. UFBs are actively removed during anaphase, and most known UFB-associated proteins are enzymes involved in DNA repair in interphase. However, little is known about the mitotic activities of these enzymes or the exact DNA structures present on UFBs. We focus on the biology of UFBs, with special emphasis on their underlying DNA structure and the decatenation machineries that process UFBs.

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Complex interactions between the DNA-damage response and mammalian telomeres

Cited by 185 publications

References 100 publications

Shared Subunits of Tetrahymena Telomerase Holoenzyme and Replication Protein A Have Different Functions in Different Cellular Complexes

Shared Subunits of Tetrahymena Telomerase Holoenzyme and Replication Protein A Have Different Functions in Different Cellular Complexes

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

Knotty Problems during Mitosis: Mechanistic Insight into the Processing of Ultrafine DNA Bridges in Anaphase

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