LIM Domain Proteins TRIP6 and LPP Associate with Shelterin to Mediate Telomere Protection
Item
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Title
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LIM Domain Proteins TRIP6 and LPP Associate with Shelterin to Mediate Telomere Protection
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Identifier
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d_2009_2013:7302fdc34886:11353
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identifier
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11665
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Creator
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Sheppard, Samantha A.,
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Contributor
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Diego Loayza
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology | Cellular biology | Genetics | LIM protein | LPP | shelterin | telomere | TRIP6 | Zyxin
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Abstract
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POT1 is the single stranded telomeric overhang binding protein of the shelterin complex, a group of six proteins essential for proper telomere function. The abrogation of POT1 DNA binding activity results in telomere elongation, or activation of the ATR DNA damage response at telomeres. Therefore, overhang binding represents the functionally relevant activity of POT1. Novel protein associations with the POT1 DNA binding domain are of great interest to explore and these possible interacting factors were sought using the yeast two-hybrid system. Bait containing the POT1 DNA binding domain was used leading to the isolation of LIM domain protein TRIP6 as a novel POT1 interacting factor. TRIP6 could co-immunoprecipitate with other shelterin components, arguing for association with the whole complex. Additionally, TRIP6 was detected at telomeres by Chromatin Immunoprecipitation and Immunofluorescence in Hela and HTC75 cells, which suggests association with telomeric DNA. TRIP6 depletion by siRNA led to the induction of telomere dysfunction induced foci, indicating a role in telomere protection. A closely related LIM protein, LPP, was also found at telomeres and was important for repressing the DNA damage response. A related LIM protein Zyxin was found not to associate with telomeres. We propose that TRIP6 and LPP represent a novel class of molecules at human telomeres involved in the repression of inappropriate DNA damage response at chromosome ends. All assays incorporate human cancer cell lines HTC75 and Hela 1.2.11. These results could advance our understanding on the repression of telomere-based senescence, an important tumor suppressor mechanism.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
