Cockayne Syndrome: Varied Requirement of Transcription-Coupled Nucleotide Excision Repair for the Removal of Three Structurally Different Adducts from Transcribed DNA

Kitsera, Nataliya; Gasteiger, Karola; Luehnsdorf, Bork; Allgayer, Julia; Epe, Bernd; Carell, Thomas and Khobta, Andriy (2014): Cockayne Syndrome: Varied Requirement of Transcription-Coupled Nucleotide Excision Repair for the Removal of Three Structurally Different Adducts from Transcribed DNA.
In: PLOS ONE 9(4), e94405

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-N-2-yl)-2- acetylaminofluorene adduct (dG(N-2)-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(N-2)-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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Chemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 1932-6203
• Language: English