Alternative lengthening of telomeres: remodeling the telomere architecture

Conomos, Dimitri; Pickett, Hilda A.; Reddel, Roger R.

doi:10.3389/fonc.2013.00027

Cited by 79 publications

(74 citation statements)

References 71 publications

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“…On the other hand, in telomerase-negative yeast cells, type I recombination amplifies the subtelomeric sequences. It is notable that, in human cells, the absence of ATRX, which we find to be mainly localized at the subtelomeres, is associated with ALT recombination (at least in all clinical samples analyzed), an event that presumably takes place only at the level of telomeric sequences, mainly involving TT AGGG repeats (46). Strikingly, ATRX is a homolog of S. cerevisiae Rad54 (47; http://www.ensembl.org) and Rad54 is essential for operating type I recombination at S. cerevisiae subtelomeres (48,49).…”

Section: Discussionmentioning

confidence: 96%

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

Eid

Demattei

Episkopou

et al. 2015

Molecular and Cellular Biology

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cMutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerasepositive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX.T he linear chromosomes of eukaryotic organisms require particular protection at their extremities. Telomeres, which represent the ends of these chromosomes and contain repeated TGrich sequences that do not code for proteins, as well as proteins of the shelterin complex, are essential for this protection (1). Telomeres protect chromosome ends from DNA repair activities that reseal chromosome internal DNA breaks occurring during DNA damage (2). Telomere sequences naturally erode with ongoing cell divisions, due to intrinsic mechanisms associated with the fixed 5=-to-3= polarity of replication of the DNA of the genome. Below a certain threshold, shortened telomeres result in DNA damageinduced cell cycle arrest, which is the equivalent of replicative senescence in cultured cells.By limiting the replicative potential of cells, telomere length acts as a biological clock, and telomere erosion serves as a barrier against tumorigenesis in healthy tissue. Paradoxically, telomere erosion or telomere dysfunction also induces chromosomal instability and favors the emergence of tumors (3). However, following cancer initiation, tumor cells must overcome the telomere-controlled replicative-senescence barrier, and all have an absolute necessity to maintain functional telomeres in order to sustain continuous and unlimited cell proliferation. In around 85 to 90% of cancer types, this occurs through upregulation of telomerase, a reverse transcriptase with a built-in RNA template specialized in telomeric DNA replication that is naturally repressed in most somatic tissues (4). In the remaining 10 to 15% of cancer types, an alternative pathway called the ALT (alternativ...

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Section: Discussionmentioning

confidence: 96%

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

Eid

Demattei

Episkopou

et al. 2015

Molecular and Cellular Biology

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“…However, in a more limited number of cases, telomere maintenance is achieved through mechanisms collectively known as ALT. [1][2][3] ALT has been documented in several species including humans, mice, chickens, C. elegans, and yeasts. [4][5][6][7][8] Approximately 15% of human cancers such as sarcomas, gastric carcinomas, central nervous system malignancies, and bladder carcinomas have activated ALT.…”

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confidence: 99%

“…12 It is commonly accepted that in the large majority of ALT tumors telomere maintenance occurs via homologous recombination (HR) between telomeric sequences. [1][2][3] In fact, several HR proteins have been found to localize to APBs and their functional inactivation leads to loss of telomeric sequences and eventually cell growth arrest or death. [1][2][3] Among these factors are the MRN complex components MRE11, RAD50 and NBS1, 13,14 which are essential for the early steps of HR, the 2 interacting proteins MUS81 and MMS4, 15 and the 2 RAD51 paralogs XRCC3 and RAD51D, which promote resolution of Holliday junctions in HR intermediates.…”

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confidence: 99%

“…These distinct traits include an extremely heterogeneous telomere length, the association of multiple telomeres in nuclear bodies containing promyelocytic leukemia (PML) to form the so-called ALT-associated PML bodies (APBs), elevated rates of exchange of telomeric sequences between newly replicated sister telomeres (telomeric sister chromatid exchange; T-SCE), abundant extrachromosomal telomeric DNA in the form of double-stranded (ds) telomeric circles (t-circles), partly single-stranded (ss) circles (C-circles and Gcircles) and linear double-stranded DNA. [1][2][3] Moreover, ALT cell lines are often characterized by the loss of expression of ATRX, which is an ATP-dependent helicase involved in chromatin remodeling, an unstable karyotype and impaired DNA damage detection and repair. 12 It is commonly accepted that in the large majority of ALT tumors telomere maintenance occurs via homologous recombination (HR) between telomeric sequences.…”

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confidence: 99%

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Telomere elongation chooses TERRA ALTernatives

Arora

Azzalin

2015

RNA Biology

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“…It is active in germ cells and stem cells (and cancer cells) but is less active or inactive in fully differentiated cells. The alternative length pathway can also maintain telomere length, and this pathway involves homologous recombination mediated DNA copying of the telomeric DNA template 15 .…”

Section: Telomere Shortening Mechanisms and Length Determinantsmentioning

confidence: 99%