Browsing by Author "Kurz, Ebba U."

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    CHD6 and the oxidative stress-induced DNA damage response
    (2018-06-21) Moore, Shaun; Goodarzi, Aaron A.; Lees-Miller, Susan; Cobb, Jennifer A.; Chan, Jennifer A. W.; Downs, Jessica A.; Kurz, Ebba U.
    Oxidative stress-induced DNA damage is a threat to the health and survival of a cell. Oxidative DNA damage responses involve nucleosome displacement, exchange or removal by ATP-dependent chromatin remodeling enzymes to promote DNA repair and transcriptional events. The CHD6 (Chromodomain, Helicase, DNA-binding 6) chromatin remodeling enzyme has been identified as an interactor of NFE2-related factor 2 (NRF2), a key transcription factor in the oxidative stress response. Several human ataxias have linkage map regions that encompass the CHD6 gene locus (20q11.1-12), while catalytically-inactive CHD6 mutant mice exhibit motor coordination defects most consistent with a cerebellar neuron disorder. Here, I describe a role for CHD6 in the response to oxidative stress-induced DNA damage. CHD6 relocates rapidly to DNA damage caused by microirradiation or KillerRed-induced oxidative stress, but not to enzyme-induced DNA double strand breaks. CHD6 interacts with poly ADP-ribose (PAR), and retention at laser microirradiation-induced DNA damage sites is PAR polymerase-dependent and prolonged by PAR Glycohydrolase depletion. I have narrowed down the PAR-interaction region of CHD6 to the extreme N-terminus and, using laser microirradiation, I have demonstrated the importance of the double chromodomain and a putative DNA-binding domain for normal recruitment to DNA-damage tracks. CHD6 protein levels are stabilized following H2O2 exposure via suppressed proteolytic degradation. Ablation of CHD6 in A549 cells using CRISPR-Cas9 led to elevated reactive oxygen species levels, created an impaired antioxidant response and a reduced ability to survive or proliferate following chronic H2O2 exposure. CHD6-deleted cells displayed elevated γH2AX and 53BP1 foci, increased ATM auto-phosphorylation and a hypersensitive G2/M checkpoint after exposure to ionizing radiation or H2O2. In conclusion, my data identify CHD6 as a novel responder to oxidative stress-induced DNA damage.