TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo.
Eladio Abreu,Elena Aritonovska,Patrick Reichenbach,Gaël Cristofari,Brad Culp,Rebecca M. Terns,Joachim Lingner,Michael P. Terns +7 more
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TLDR
The 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.Abstract:
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.read more
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Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions.
TL;DR: ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous, and generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.
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Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway.
Courtney A. Lovejoy,Wendi Li,Steven Reisenweber,Supawat Thongthip,Joanne Bruno,Titia de Lange,Saurav De,John H.J. Petrini,Patricia Sung,Maria Jasin,Joseph Rosenbluh,Yaara Zwang,Yaara Zwang,Barbara A. Weir,Charlie Hatton,Elena Ivanova,Laura E. MacConaill,Megan Hanna,William C. Hahn,William C. Hahn,Neal F. Lue,Roger R. Reddel,Roger R. Reddel,Yuchen Jiao,Kenneth W. Kinzler,Bert Vogelstein,Nickolas Papadopoulos,Alan K. Meeker +27 more
TL;DR: It is shown that loss of ATRX protein and mutations in the ATRRX gene are hallmarks of ALT–immortalized cell lines, and these attributes will facilitate the diagnosis and treatment ofALT positive human cancers.
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Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins
Paula Martínez,Maria A. Blasco +1 more
TL;DR: 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 is discussed.
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Telomeres in cancer: tumour suppression and genome instability
John Maciejowski,Titia de Lange +1 more
TL;DR: Current data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomeres crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
Journal ArticleDOI
Finding the end: recruitment of telomerase to telomeres
TL;DR: Insight is provided into the mechanisms of telomerase recruitment to telomeres, highlighting the contribution of telomere-associated proteins, including TPP1 in humans, Ccq1 in Schizosaccharomyces pombe and Cdc13 and Ku70–Ku80 in Saccharomyceces cerevisiae.
References
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Andrea G. Bodnar,Michel M. Ouellette,Maria Frolkis,Shawn E. Holt,Choy-Pik Chiu,Gregg B. Morin,Calvin B. Harley,Jerry W. Shay,Serge Lichtsteiner,Woodring E. Wright +9 more
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Journal ArticleDOI
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Fabrizio d'Adda di Fagagna,Philip Michael Reaper,Lorena Clay-Farrace,Heike Fiegler,Philippa Carr,Thomas von Zglinicki,Gabriele Saretzki,Nigel P. Carter,Stephen P. Jackson +8 more
TL;DR: It is proposed that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.
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How Shelterin Protects Mammalian Telomeres
Wilhelm Palm,Titia de Lange +1 more
TL;DR: Recent experiments have revealed how shelterin represses the ATM and ATR kinase signaling pathways and hides chromosome ends from nonhomologous end joining and homology-directed repair.
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A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis.
TL;DR: The essential RNA component of this ribonucleoprotein enzyme has now been cloned and found to contain the sequence CAACCCCAA, which seems to be the template for the synthesis of TTGGGG repeats.