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8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury

Pan, Lang ; Hao, Wenjing ; Xue, Yaoyao ; Wang, Ke ; Zheng, Xu ; Luo, Jixian ; Ba, Xueqing ; Xiang, Yang ; Qin, Xiaoqun and Bergwik, Jesper LU , et al. (2023) In Nucleic Acids Research 51(3). p.1087-1102
Abstract

Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors,... (More)

Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
51
issue
3
pages
16 pages
publisher
Oxford University Press
external identifiers
  • pmid:36651270
  • scopus:85159961134
ISSN
0305-1048
DOI
10.1093/nar/gkac1241
language
English
LU publication?
yes
id
f2b7a711-9f3a-40fd-a891-379e80e49c7f
date added to LUP
2023-08-23 12:57:56
date last changed
2024-04-20 01:21:08
@article{f2b7a711-9f3a-40fd-a891-379e80e49c7f,
  abstract     = {{<p>Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.</p>}},
  author       = {{Pan, Lang and Hao, Wenjing and Xue, Yaoyao and Wang, Ke and Zheng, Xu and Luo, Jixian and Ba, Xueqing and Xiang, Yang and Qin, Xiaoqun and Bergwik, Jesper and Tanner, Lloyd and Egesten, Arne and Brasier, Allan R. and Boldogh, Istvan}},
  issn         = {{0305-1048}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  pages        = {{1087--1102}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury}},
  url          = {{http://dx.doi.org/10.1093/nar/gkac1241}},
  doi          = {{10.1093/nar/gkac1241}},
  volume       = {{51}},
  year         = {{2023}},
}