https://www.cell.com/molecular-cell/pdf/S1097-2765(11)00680-0.pdf

Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions.

The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT–immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.

/pdf/loss-of-atrx-genome-instability-and-an-altered-dna-damage-3lzfpi94xq.pdf

Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.

Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends Telomere elongation is carried out by telomerase Telomerase can also act as a transcriptional modulator of the Wnt-β-catenin signalling pathway and has RNA-dependent RNA polymerase activity Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites

Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins

The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.

/pdf/telomeres-in-cancer-tumour-suppression-and-genome-5bxrjhhbcs.pdf

Telomeres in cancer: tumour suppression and genome instability

Unicellular eukaryotes and mammalian germ cells and stem cells can maintain their telomere length through the action of telomerase. Insights into the mechanism by which telomerase is recruited to capped telomeres, and the individual contributions of telomere-associated proteins, highlight differences in this process between humans, budding yeast and fission yeast.

Finding the end: recruitment of telomerase to telomeres

Recruitment to telomeres is a pivotal step in the function and regulation of human telomerase; however, the molecular basis for recruitment is not known. Here, we have directly investigated the process of telomerase recruitment via fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP). We find that depletion of two components of the shelterin complex that is found at telomeres—TPP1 and the protein that tethers TPP1 to the complex, TIN2—results in a loss of telomerase recruitment. On the other hand, we find that the majority of the observed telomerase association with telomeres does not require POT1, the shelterin protein that links TPP1 to the single-stranded region of the telomere. Deletion of the oligonucleotide/oligosaccharide binding fold (OB-fold) of TPP1 disrupts telomerase recruitment. In addition, while loss of TPP1 results in the appearance of DNA damage factors at telomeres, the DNA damage response per se does not account for the telomerase recruitment defect observed in the absence of TPP1. Our findings indicate that TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells and that recruitment does not depend on POT1 or interaction of the shelterin complex with the single-stranded region of the telomere.

Brad Culp

Papers

TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo.