Abstract |
Hereditary defects in the transcription-coupled nucleotide excision repair (TC-NER) pathway of damaged DNA cause severe neurodegenerative disease Cockayne syndrome (CS), however the origin and chemical nature of the underlying DNA damage had remained unknown. To find out, to which degree the structural properties of DNA lesions determine the extent of transcription arrest in human CS cells, we performed quantitative host cell reactivation analyses of expression vectors containing various synthetic adducts. We found that a single 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene adduct (dG(N2)-AAF) constitutes an unsurmountable obstacle to transcription in both CS-A and CS-B cells and is removed exclusively by the CSA- and CSB-dependent pathway. In contrast, contribution of the CS proteins to the removal of two other transcription-blocking DNA lesions - N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG(C8)-AAF) and cyclobutane thymine- thymine (TT) dimer - is only minor (TT dimer) or none (dG(C8)-AAF). The unique properties of dG(N2)-AAF identify this adduct as a prototype for a new class of DNA lesions that escape the alternative global genome repair and could be critical for the CS pathogenesis.
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Authors | Nataliya Kitsera, Karola Gasteiger, Bork Lühnsdorf, Julia Allgayer, Bernd Epe, Thomas Carell, Andriy Khobta |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 4
Pg. e94405
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24713864
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene
- DNA Adducts
- Fluorenes
- Poly-ADP-Ribose Binding Proteins
- DNA Helicases
- ERCC6 protein, human
- DNA Repair Enzymes
- Deoxyguanosine
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Topics |
- Cell Line
- Cockayne Syndrome
(genetics)
- DNA Adducts
- DNA Helicases
(genetics, metabolism)
- DNA Repair
- DNA Repair Enzymes
(genetics, metabolism)
- Deoxyguanosine
(analogs & derivatives, pharmacology)
- Fluorenes
(pharmacology)
- Gene Expression Regulation
(drug effects)
- Gene Silencing
(drug effects)
- Genes, Reporter
- Humans
- Poly-ADP-Ribose Binding Proteins
- Transcription, Genetic
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