Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair.

Corina Penterling,Kristian Unger,Günther Dollinger,Claudia Böhland,Judith Reindl,Christoph Greubel,Kerstin Borgmann,Christian Siebenwirth,Herbert Braselmann,Christina Wilke,Anna A Friedl,Randolph B Caldwell,Ramona Stamp,Guido A Drexler,Stefanie Girst,Wael Y Mansour

doi:10.1371/journal.pone.0156599

Abstract

Histone demethylases have recently gained interest as potential targets in cancer treatment and several histone demethylases have been implicated in the DNA damage response. We investigated the effects of siRNA-mediated depletion of histone demethylase Jarid1A (KDM5A, RBP2), which demethylates transcription activating tri- and dimethylated lysine 4 at histone H3 (H3K4me3/me2), on growth characteristics and cellular response to radiation in several cancer cell lines. In unirradiated cells Jarid1A depletion lead to histone hyperacetylation while not affecting cell growth. In irradiated cells, depletion of Jarid1A significantly increased cellular radiosensitivity. Unexpectedly, the hyperacetylation phenotype did not lead to disturbed accumulation of DNA damage response and repair factors 53BP1, BRCA1, or Rad51 at damage sites, nor did it influence resolution of radiation-induced foci or rejoining of reporter constructs. We conclude that the radiation sensitivity observed following depletion of Jarid1A is not caused by a deficiency in repair of DNA double-strand breaks.

Highlights

Chromatin structure plays a key role in the regulation of transcription, replication and repair
We investigated the effects of siRNA-mediated depletion of histone demethylase Jarid1A (KDM5A, RBP2), which demethylates transcription activating tri- and dimethylated lysine 4 at histone H3 (H3K4me3/me2), on growth characteristics and cellular response to radiation in several cancer cell lines
In the present work we investigated the role of histone demethylase Jarid1A in cell proliferation and radiation response by siRNA-mediated depletion of Jarid1A

Summary

Introduction

Chromatin structure plays a key role in the regulation of transcription, replication and repair. Deregulation of pathways regulating the epigenome and chromatin structure is an important factor in development of disease, including cancer [1,2]. Cancer cells exhibit characteristic alterations in chromatin structure [3] and recent sequencing analyses of cancer genomes have. Jarid1A in Cell Growth and Radiation Response collection, decision to publish, or preparation of the manuscript

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