Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription
Open Access
- 21 August 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (36), 22183-22192
- https://doi.org/10.1073/pnas.1919445117
Abstract
Among several reversible epigenetic changes occurring during transcriptional activation, only demethylation of histones and cytosine-phosphate-guanines (CpGs) in gene promoters and other regulatory regions by specific demethylase(s) generates reactive oxygen species (ROS), which oxidize DNA and other cellular components. Here, we show induction of oxidized bases and single-strand breaks (SSBs), but not direct double-strand breaks (DSBs), in the genome during gene activation by ligands of the nuclear receptor superfamily. We observed that these damages were preferentially repaired in promoters via the base excision repair (BER)/single-strand break repair (SSBR) pathway. Interestingly, BER/SSBR inhibition suppressed gene activation. Constitutive association of demethylases with BER/SSBR proteins in multiprotein complexes underscores the coordination of histone/DNA demethylation and genome repair during gene activation. However, ligand-independent transcriptional activation occurring during heat shock (HS) induction is associated with the generation of DSBs, the repair of which is likewise essential for the activation of HS-responsive genes. These observations suggest that the repair of distinct damages induced during diverse transcriptional activation is a universal prerequisite for transcription initiation. Because of limited investigation of demethylation-induced genome damage during transcription, this study suggests that the extent of oxidative genome damage resulting from various cellular processes is substantially underestimated.Funding Information
- HHS | NIH | National Cancer Institute (R01 CA158910)
- HHS | NIH | National Cancer Institute (P01 CA092584)
- HHS | NIH | National Institute of General Medical Sciences (R01 GM105090)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS088645)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (RF1 NS112719)
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