The CHD6 chromatin remodeler is an oxidative DNA damage response factor

Shaun Moore,Jennifer A Chan,David C Schriemer,Shujuan Fang,Zachary D Nagel,Christoph U Schräder,Haico Van Attikum,Fintan K T Stanley,N Daniel Berger,Cortt G Piett,Martijn S Luijsterburg,Aaron A Goodarzi

doi:10.1038/s41467-018-08111-y

Abstract

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes. Here, we show that Chromodomain Helicase DNA-binding protein 6 (CHD6), distinct to other CHD enzymes, is stabilized during oxidative stress via reduced degradation. CHD6 relocates rapidly to DNA damage in a manner dependent upon oxidative lesions and a conserved N-terminal poly(ADP-ribose)-dependent recruitment motif, with later retention requiring the double chromodomain and central core. CHD6 ablation increases reactive oxygen species persistence and impairs anti-oxidant transcriptional responses, leading to elevated DNA breakage and poly(ADP-ribose) induction that cannot be rescued by catalytic or double chromodomain mutants. Despite no overt epigenetic or DNA repair abnormalities, CHD6 loss leads to impaired cell survival after chronic oxidative stress, abnormal chromatin relaxation, amplified DNA damage signaling and checkpoint hypersensitivity. We suggest that CHD6 is a key regulator of the oxidative DNA damage response.

Highlights

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes
Whole cell extracts of A549 cells grown to confluence in either 3% or ambient (21%) O2 were immunoblotted for Chromodomain Helicase DNA-binding protein 6 (CHD6), p53 and actin (Fig. 1a)
We examined whether CHD1, CHD2, CHD3.1 or CHD4, the chromodomainhelicase-DNA binding (CHD) enzymes previously described to have a role in the DNA damage response, displayed dynamic alteration in expression under the same conditions (Fig. 1b, c)

Summary

Introduction

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes. Chromatin remodeling enzymes adjust nucleosome spacing to regulate DNA accessibility and transcription in response to stimuli, and are essential components of DNA damage responses that are altered often in cancer[1]. The nine-member family of chromodomainhelicase-DNA binding (CHD) chromatin remodeling enzymes is characterized by the double chromodomain and a central ATPase-helicase domain that confers nucleosome respacing, removal or exchange activity[2]. We present evidence that CHD6 stabilizes during oxidative stress, relocates dynamically to sites of oxidative DNA damage and is a key component of the signaling and transcriptional response to reactive oxygen species (ROS) exposure. We define a mechanism by which cell survival in oxidatively stressed human cells is driven by the chromatin remodeler CHD6

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Results

Conclusion