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Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway

The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previous...

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Autores principales: Awwad, Samah W., Ayoub, Nabieh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400592/
https://www.ncbi.nlm.nih.gov/pubmed/25770186
http://dx.doi.org/10.1242/bio.201410991
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author Awwad, Samah W.
Ayoub, Nabieh
author_facet Awwad, Samah W.
Ayoub, Nabieh
author_sort Awwad, Samah W.
collection PubMed
description The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3. Consequently, we demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. Furthermore, we show that the defective MMR in cells overexpressing KDM4C is mainly due to the increase in its demethylase activity and can be mended by KDM4C downregulation. Altogether, our data suggest that cells overexpressing KDM4A-C are defective in DNA MMR and this may contribute to genomic instability and tumorigenesis.
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spelling pubmed-44005922015-04-24 Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway Awwad, Samah W. Ayoub, Nabieh Biol Open Research Article The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3. Consequently, we demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. Furthermore, we show that the defective MMR in cells overexpressing KDM4C is mainly due to the increase in its demethylase activity and can be mended by KDM4C downregulation. Altogether, our data suggest that cells overexpressing KDM4A-C are defective in DNA MMR and this may contribute to genomic instability and tumorigenesis. The Company of Biologists 2015-03-13 /pmc/articles/PMC4400592/ /pubmed/25770186 http://dx.doi.org/10.1242/bio.201410991 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Awwad, Samah W.
Ayoub, Nabieh
Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title_full Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title_fullStr Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title_full_unstemmed Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title_short Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway
title_sort overexpression of kdm4 lysine demethylases disrupts the integrity of the dna mismatch repair pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400592/
https://www.ncbi.nlm.nih.gov/pubmed/25770186
http://dx.doi.org/10.1242/bio.201410991
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