Alternative lengthening of telomeres: models, mechanisms and implications

  title={Alternative lengthening of telomeres: models, mechanisms and implications},
  author={Anthony J. Cesare and Roger R. Reddel},
  journal={Nature Reviews Genetics},
Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10–15% of cancers — including some with particularly poor outcome — it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the… 

Alternative lengthening of telomeres: remodeling the telomere architecture

It is speculated that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype, and current findings about telomeres structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state are reviewed.

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

The recent progress in the mechanistic studies of ALT is reviewed, the emerging therapeutic strategies to target ALT-positive cancers are discussed, and an attractive target for cancer therapy is discussed.

PML body meets telomere

It is concluded that APBs are important functional intermediates in what is considered the canonical ALT pathway and deregulations of cellular pathways that contribute to the emergence of the ALT phenotype are discussed.

DNA repair: Telomere-lengthening mechanism revealed

Roger Greenberg and colleagues show here that a specialized replisome is formed in ALT-positive cancer cells that is capable of synthesizing long tracts of DNA at the telomere, proceeding from a double-strand break.

Systematic Characterization of the Molecular Mechanisms That Regulate and Mediate Alternative Lengthening of Telomeres in Breast Carcinoma

Progress is reported on in profiling the global transcriptional patterns that differentially characterize ALT+ cells and the analytical tools used to define an ALT-related gene signature, and the efforts to identify potential functional relationship to ALT activity.

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

It is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism, suggesting that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

Alternative paths to telomere elongation.

Molecular mechanisms of activity and derepression of alternative lengthening of telomeres

Alternative lengthening of telomeres (ALT) involves homology-directed telomere synthesis and dissolution of HR intermediates, which culminates in dissolution ofHR intermediates.



Telomere uncapping and alternative lengthening of telomeres

DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity

It is shown that partially single-stranded telomeric (CCCTAA)n DNA circles (C-circles) are ALT specific, and the C-circle assay (CC assay) may have clinical utility for diagnosis and management of ALT+ tumors.

Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex

It is demonstrated here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs, which resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling.

Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells.

Short hairpin RNAs directed at either Xrcc3 or Nbs1, two proteins involved in the homologous recombination pathway, are used to determine the role of these proteins in t circle production and the requirement of t circles in maintaining the ALT pathway.

The first molecular details of ALT in human tumor cells.

It is suggested that ALT in human tumors is a dysregulated version of an aspect of normal mammalian telomere homeostasis, which may be a vestige of the TMM used by ancient eukaryotes.

Alternative lengthening of telomeres in mammalian cells

The existence of ALT adds some complexity to proposed uses of telomere-related parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomeres maintenance.

Telomeric Recombination in Mismatch Repair Deficient Human Colon Cancer Cells after Telomerase Inhibition

This is the first report of inducing a telomerase-independent telomere elongation in human cancer cells when telomersase is inhibited, thus describing a novel mechanism of resistance to antitelomerase therapy.

Telomere recombination requires the MUS81 endonuclease

It is demonstrated that MUS81, a DNA structure specific recombination endonuclease, has a key role in the maintenance of telomeres in human ALT cells.

Alternative Lengthening of Telomeres Is Characterized by High Rates of Telomeric Exchange

Using chromosome orientation fluorescence in situ hybridization, it is found that postreplicative exchange events involving a telomere and another TTAGGG-repeat tract occur at remarkably high frequencies in ALT cells and rarely or never in non-ALT cells, including cell lines with very long telomeres.

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.

The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.