Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 16, Pages 8537-8547Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz558
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Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [KH 263/1, KH263/2, KH263/5, SFB1631 INST 247/926]
- Ressort Forschung und Lehre, University Medical Center of the Johannes Gutenberg University Mainz
- European Union (EU) [ESF/14-BM-A55]
- Damp Foundation [2017-05]
- International PhD Programme (IPP) Mainz
- DFG, German Research Foundation
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Apurinic/apyrimidinic (AP) sites are a class of highly mutagenic and toxic DNA lesions arising in the genome from a number of exogenous and endogenous sources. Repair of AP lesions takes place predominantly by the base excision pathway (BER). However, among chemically heterogeneous AP lesions formed in DNA, some are resistant to the endonuclease APE1 and thus refractory to BER. Here, we employed two types of reporter constructs accommodating synthetic APE1-resistant AP lesions to investigate the auxiliary repair mechanisms in human cells. By combined analyses of recovery of the transcription rate and suppression of transcriptional mutagenesis at specifically positioned AP lesions, we demonstrate that nucleotide excision repair pathway (NER) efficiently removes BER-resistant AP lesions and significantly enhances the repair of APE1-sensitive ones. Our results further indicate that core NER components XPA and XPF are equally required and that both global genome (GG-NER) and transcription coupled (TC-NER) subpathways contribute to the repair.
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