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      TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity

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          Abstract

          TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TIN2 on telomerase activity. We identified a new isoform in human cells, TIN2M, that is expressed at levels similar to those of previously studied TIN2 isoforms.

          ABSTRACT

          TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TIN2 on telomerase activity. We identified a new isoform in human cells, TIN2M, that is expressed at levels similar to those of previously studied TIN2 isoforms. All three TIN2 isoforms localized to and maintained telomere integrity in vivo, and localization was not disrupted by telomere syndrome mutations. Using direct telomerase activity assays, we discovered that TIN2 stimulated telomerase processivity in vitro. All of the TIN2 isoforms stimulated telomerase to similar extents. Mutations in the TPP1 TEL patch abrogated this stimulation, suggesting that TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. We conclude from our data and previously published work that TIN2/TPP1/POT1 is a functional shelterin subcomplex.

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          Most cited references 39

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          The telomere syndromes.

          There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.
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            PRALINE: a multiple sequence alignment toolbox that integrates homology-extended and secondary structure information

            PRofile ALIgNEment (PRALINE) is a fully customizable multiple sequence alignment application. In addition to a number of available alignment strategies, PRALINE can integrate information from database homology searches to generate a homology-extended multiple alignment. PRALINE also provides a choice of seven different secondary structure prediction programs that can be used individually or in combination as a consensus for integrating structural information into the alignment process. The program can be used through two separate interfaces: one has been designed to cater to more advanced needs of researchers in the field, and the other for standard construction of high confidence alignments. The web-based output is designed to facilitate the comprehensive visualization of the generated alignments by means of five default colour schemes based on: residue type, position conservation, position reliability, residue hydrophobicity and secondary structure, depending on the options set. A user can also define a custom colour scheme by selecting which colour will represent one or more amino acids in the alignment. All generated alignments are also made available in the PDF format for easy figure generation for publications. The grouping of sequences, on which the alignment is based, can also be visualized as a dendrogram. PRALINE is available at .
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              GWIPS-viz: development of a ribo-seq genome browser

              We describe the development of GWIPS-viz (http://gwips.ucc.ie), an online genome browser for viewing ribosome profiling data. Ribosome profiling (ribo-seq) is a recently developed technique that provides genome-wide information on protein synthesis (GWIPS) in vivo. It is based on the deep sequencing of ribosome-protected messenger RNA (mRNA) fragments, which allows the ribosome density along all mRNA transcripts present in the cell to be quantified. Since its inception, ribo-seq has been carried out in a number of eukaryotic and prokaryotic organisms. Owing to the increasing interest in ribo-seq, there is a pertinent demand for a dedicated ribo-seq genome browser. GWIPS-viz is based on The University of California Santa Cruz (UCSC) Genome Browser. Ribo-seq tracks, coupled with mRNA-seq tracks, are currently available for several genomes: human, mouse, zebrafish, nematode, yeast, bacteria (Escherichia coli K12, Bacillus subtilis), human cytomegalovirus and bacteriophage lambda. Our objective is to continue incorporating published ribo-seq data sets so that the wider community can readily view ribosome profiling information from multiple studies without the need to carry out computational processing.
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                Author and article information

                Journal
                Mol Cell Biol
                Mol. Cell. Biol
                mcb
                mcb
                MCB
                Molecular and Cellular Biology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0270-7306
                1098-5549
                5 August 2019
                11 October 2019
                1 November 2019
                11 October 2019
                : 39
                : 21
                Affiliations
                [a ]Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [b ]Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [c ]Graduate Program in Biochemistry Cell and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                Author notes
                Address correspondence to Carol W. Greider, cgreider@ 123456jhmi.edu .
                [*]

                Present address: Alexandra M. Pike, MIT Department of Biology, Cambridge, Massachusetts, USA.

                Citation Pike AM, Strong MA, Ouyang JPT, Greider CW. 2019. TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. Mol Cell Biol 39:e00593-18. https://doi.org/10.1128/MCB.00593-18.

                Article
                00593-18
                10.1128/MCB.00593-18
                6791651
                31383750
                Copyright © 2019 Pike et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                Page count
                supplementary-material: 1, Figures: 8, Tables: 0, Equations: 0, References: 70, Pages: 15, Words: 8812
                Product
                Funding
                Funded by: HHS | National Institutes of Health (NIH), https://doi.org/10.13039/100000002;
                Award ID: R37AG009383
                Award ID: R35CA209974
                Award Recipient :
                Categories
                Research Article
                Spotlight
                Custom metadata
                November 2019

                Molecular biology

                telomere, telomerase, shelterin, processivity, alternative splicing, tpp1, tin2, pot1

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