The CHD6 chromatin remodeler is an oxidative DNA damage response factor

Shaun Moore, N. Daniel Berger, Martijn S. Luijsterburg, Cortt G. Piett, Fintan K. T. Stanley, Christoph U. Schräder, Shujuan Fang, Jennifer A. Chan, David C. Schriemer, Zachary D. Nagel, Haico Attikum and Aaron A. Goodarzi ()
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Shaun Moore: University of Calgary
N. Daniel Berger: University of Calgary
Martijn S. Luijsterburg: Leiden University Medical Center
Cortt G. Piett: School of Public Health
Fintan K. T. Stanley: University of Calgary
Christoph U. Schräder: University of Calgary
Shujuan Fang: University of Calgary
Jennifer A. Chan: University of Calgary
David C. Schriemer: University of Calgary
Zachary D. Nagel: School of Public Health
Haico Attikum: Leiden University Medical Center
Aaron A. Goodarzi: University of Calgary

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08111-y

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