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TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response

Despite advances in our understanding of protein kinase regulation in the DNA damage response, the mechanism that controls protein phosphatase activity in this pathway is unclear. Unlike kinases, the activity and specificity of serine/threonine phosphatases is governed largely by their associated pr...

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Autores principales: Rosales, Kimberly Romero, Reid, Michael A., Yang, Ying, Tran, Thai Q., Wang, Wen-I, Lowman, Xazmin, Pan, Min, Kong, Mei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696667/
https://www.ncbi.nlm.nih.gov/pubmed/26717153
http://dx.doi.org/10.1371/journal.pone.0145938
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author Rosales, Kimberly Romero
Reid, Michael A.
Yang, Ying
Tran, Thai Q.
Wang, Wen-I
Lowman, Xazmin
Pan, Min
Kong, Mei
author_facet Rosales, Kimberly Romero
Reid, Michael A.
Yang, Ying
Tran, Thai Q.
Wang, Wen-I
Lowman, Xazmin
Pan, Min
Kong, Mei
author_sort Rosales, Kimberly Romero
collection PubMed
description Despite advances in our understanding of protein kinase regulation in the DNA damage response, the mechanism that controls protein phosphatase activity in this pathway is unclear. Unlike kinases, the activity and specificity of serine/threonine phosphatases is governed largely by their associated proteins. Here we show that Tip41-like protein (TIPRL), an evolutionarily conserved binding protein for PP2A-family phosphatases, is a negative regulator of protein phosphatase 4 (PP4). Knockdown of TIPRL resulted in increased PP4 phosphatase activity and formation of the active PP4-C/PP4R2 complex known to dephosphorylate γ-H2AX. Thus, overexpression of TIPRL promotes phosphorylation of H2AX, and increases γ-H2AX positive foci in response to DNA damage, whereas knockdown of TIPRL inhibits γ-H2AX phosphorylation. In correlation with γ-H2AX levels, we found that TIPRL overexpression promotes cell death in response to genotoxic stress, and knockdown of TIPRL protects cells from genotoxic agents. Taken together, these data demonstrate that TIPRL inhibits PP4 activity to allow for H2AX phosphorylation and the subsequent DNA damage response.
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spelling pubmed-46966672016-01-13 TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response Rosales, Kimberly Romero Reid, Michael A. Yang, Ying Tran, Thai Q. Wang, Wen-I Lowman, Xazmin Pan, Min Kong, Mei PLoS One Research Article Despite advances in our understanding of protein kinase regulation in the DNA damage response, the mechanism that controls protein phosphatase activity in this pathway is unclear. Unlike kinases, the activity and specificity of serine/threonine phosphatases is governed largely by their associated proteins. Here we show that Tip41-like protein (TIPRL), an evolutionarily conserved binding protein for PP2A-family phosphatases, is a negative regulator of protein phosphatase 4 (PP4). Knockdown of TIPRL resulted in increased PP4 phosphatase activity and formation of the active PP4-C/PP4R2 complex known to dephosphorylate γ-H2AX. Thus, overexpression of TIPRL promotes phosphorylation of H2AX, and increases γ-H2AX positive foci in response to DNA damage, whereas knockdown of TIPRL inhibits γ-H2AX phosphorylation. In correlation with γ-H2AX levels, we found that TIPRL overexpression promotes cell death in response to genotoxic stress, and knockdown of TIPRL protects cells from genotoxic agents. Taken together, these data demonstrate that TIPRL inhibits PP4 activity to allow for H2AX phosphorylation and the subsequent DNA damage response. Public Library of Science 2015-12-30 /pmc/articles/PMC4696667/ /pubmed/26717153 http://dx.doi.org/10.1371/journal.pone.0145938 Text en © 2015 Rosales et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rosales, Kimberly Romero
Reid, Michael A.
Yang, Ying
Tran, Thai Q.
Wang, Wen-I
Lowman, Xazmin
Pan, Min
Kong, Mei
TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title_full TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title_fullStr TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title_full_unstemmed TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title_short TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response
title_sort tiprl inhibits protein phosphatase 4 activity and promotes h2ax phosphorylation in the dna damage response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696667/
https://www.ncbi.nlm.nih.gov/pubmed/26717153
http://dx.doi.org/10.1371/journal.pone.0145938
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