Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling

Leopoldo Aguilera-Aguirre, Koa Hosoki, Attila Bacsi, Zsolt Radák, Sanjiv Sur, Muralidhar L. Hegde, Bing Tian, Alfredo Saavedra-Molina, Allan R. Brasier, Xueqing Ba, Istvan Boldogh

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) generated by environmental exposures, and endogenously as by-products of respiration, oxidatively modify biomolecules including DNA. Accumulation of ROS-induced DNA damage has been implicated in various diseases that involve inflammatory processes, and efficient DNA repair is considered critical in preventing such diseases. One of the most abundant DNA base lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which is repaired by the 8-oxoguanine DNA glycosylase 1 (OGG1)-initiated base-excision repair (OGG1-BER) pathway. Recent studies have shown that the OGG1-BER by-product 8-oxoG base forms a complex with cytosolic OGG1, activating small GTPases and downstream cell signaling in cultured cells and lungs. This implies that persistent OGG1-BER could result in signaling leading to histological changes in airways. To test this, we mimicked OGG1-BER by repeatedly challenging airways with its repair product 8-oxoG base. Gene expression was analyzed by RNA sequencing (RNA-Seq) and qRT-PCR, and datasets were evaluated by gene ontology and statistical tools. RNA-Seq analysis identified 3252 differentially expressed transcripts (2435 up- and 817 downregulated, ≥ 3-fold change). Among the upregulated transcripts, 2080 mRNAs were identified whose encoded protein products were involved in modulation of the actin family cytoskeleton, extracellular matrix, cell adhesion, cadherin, and cell junctions, affecting biological processes such as tissue development, cell-to-cell adhesion, cell communication, and the immune system. These data are supported by histological observations showing epithelial alterations, subepithelial fibrosis, and collagen deposits in the lungs. These data imply that continuous challenge by the environment and consequent OGG1-BER-driven signaling trigger gene expression consistent with airway remodeling.

Original languageEnglish (US)
Pages (from-to)20-33
Number of pages14
JournalFree Radical Biology and Medicine
Volume89
DOIs
StatePublished - Dec 1 2015

Fingerprint

DNA Glycosylases
Airway Remodeling
Gene Expression Profiling
DNA Repair
Repair
DNA
RNA Sequence Analysis
Cell adhesion
Gene expression
Cell Adhesion
Byproducts
Reactive Oxygen Species
RNA
Cell signaling
Biological Phenomena
Gene Expression
Lung
Gene Ontology
Intercellular Junctions
Monomeric GTP-Binding Proteins

Keywords

  • 8-Oxoguanine
  • Airway remodeling
  • OGG1-BER

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling. / Aguilera-Aguirre, Leopoldo; Hosoki, Koa; Bacsi, Attila; Radák, Zsolt; Sur, Sanjiv; Hegde, Muralidhar L.; Tian, Bing; Saavedra-Molina, Alfredo; Brasier, Allan R.; Ba, Xueqing; Boldogh, Istvan.

In: Free Radical Biology and Medicine, Vol. 89, 01.12.2015, p. 20-33.

Research output: Contribution to journalArticle

Aguilera-Aguirre, L, Hosoki, K, Bacsi, A, Radák, Z, Sur, S, Hegde, ML, Tian, B, Saavedra-Molina, A, Brasier, AR, Ba, X & Boldogh, I 2015, 'Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling', Free Radical Biology and Medicine, vol. 89, pp. 20-33. https://doi.org/10.1016/j.freeradbiomed.2015.07.007
Aguilera-Aguirre, Leopoldo ; Hosoki, Koa ; Bacsi, Attila ; Radák, Zsolt ; Sur, Sanjiv ; Hegde, Muralidhar L. ; Tian, Bing ; Saavedra-Molina, Alfredo ; Brasier, Allan R. ; Ba, Xueqing ; Boldogh, Istvan. / Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling. In: Free Radical Biology and Medicine. 2015 ; Vol. 89. pp. 20-33.
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