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Sequence specific oxidative DNA modifications in the mitochondrial genome of hypoxic human bronchial epithelial and pulmonary artery endothelial cells
Author(s) -
Ruchko Mykhaylo V.,
Gorodnya Olenna M.,
Pastukh Viktor M.,
Gillespie Mark N.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1002.14
Subject(s) - mitochondrial dna , biology , transcription (linguistics) , oxidative phosphorylation , gene , mitochondrion , hypoxia (environmental) , dna , microbiology and biotechnology , genetics , chemistry , biochemistry , oxygen , linguistics , philosophy , organic chemistry
Reactive oxygen species used as second messengers in hypoxic signaling oxidatively modify specific bases within hypoxic response elements (HREs) of hypoxia inducible genes (FRBM, 43: 1616, 2007). Because oxidative lesions are restricted to HREs associated with transcriptionally‐active nucleosomes, and since model base modifications influence transcription complex assembly and reporter gene expression, we proposed that controlled oxidative DNA damage and repair in HREs may regulate transcription in hypoxia (AJP‐Lung, 292: L1, 2007). Whether hypoxia causes modifications in transcriptional regulatory sequences of the mitochondrial genome is unknown. Accordingly, we used quantitative Southern blot analyses to detect oxidative base modifications in a 13.8kb mtDNA sequence containing the "fragile region" incriminated in mitochondrial diseases and a 2.7kb sequence containing the D‐loop control region. In human airways epithelial and pulmonary arterial endothelial cells, we found that whereas hypoxia failed to cause lesions in the larger mtDNA sequence, the D‐loop‐containing sequence displayed modifications early after hypoxic exposure that were subsequently removed despite persistent hypoxia. These observations support the intriguing idea that controlled oxidative DNA damage and repair in the D‐loop region may influence mtDNA replication and/or transcription in hypoxia.