The CHD6 chromatin remodeler is an oxidative DNA damage response factor

Nat Commun. 2019 Jan 16;10(1):241. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cell Survival / physiology
  • Chromatin Assembly and Disassembly / physiology*
  • DNA Damage / physiology*
  • DNA Damage / radiation effects
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair / physiology*
  • G2 Phase Cell Cycle Checkpoints / physiology
  • G2 Phase Cell Cycle Checkpoints / radiation effects
  • HEK293 Cells
  • Humans
  • Intravital Microscopy
  • Lasers / adverse effects
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oxidative Stress / physiology*
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • CHD6 protein, human
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • DNA Helicases