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Title: Mitochondrial Transcription Factor A Binds to and Promotes Mutagenic Transcriptional Bypass of O4-Alkylthymidine Lesions.

Authors: He, Xiaomei; Wang, Pengcheng; Wang, Yinsheng

Published In Anal Chem, (2021 01 19)

Abstract: O2- and O4-alkylated thymidine lesions are known to be poorly repaired and persist in mammalian tissues. To understand how mammalian cells sense the presence and regulate the repair of these lesions, we employed a quantitative proteomic method to discover regioisomeric O2- and O4-n-butylthymidine (O2- and O4-nBudT)-binding proteins. We were able to identify 21 and 74 candidate DNA damage recognition proteins for O2-nBudT- and O4-nBudT-bearing DNA probes, respectively. Among these proteins, DDB1 and DDB2 selectively bind to O2-nBudT-containing DNA, whereas three high-mobility group (HMG) proteins (i.e., HMGB1, HMGB2, and mitochondrial transcription factor A (TFAM)) exhibit preferential binding to O4-nBudT-bearing DNA. We further demonstrated that TFAM binds directly and selectively with O4-alkyldT-harboring DNA, and the binding capacity depends mainly on the HMG box-A domain of TFAM. We also found that TFAM promotes transcriptional mutagenesis of O4-nBudT and O4-pyridyloxobutylthymidine, which is a DNA adduct induced by tobacco-specific N-nitrosamines, in vitro and in human cells. Together, we explored, for the first time, the interaction proteomes of O-alkyldT lesions, and our study expanded the functions of TFAM by revealing its capability in the recognition of O4-alkyldT-bearing DNA and uncovering its modulation of transcriptional mutagenesis of these lesions in human cells.

PubMed ID: 33290046 Exiting the NIEHS site

MeSH Terms: Binding Sites; DNA-Binding Proteins/chemistry*; DNA-Binding Proteins/metabolism; DNA/chemistry; DNA/genetics; DNA/metabolism; Humans; Mitochondrial Proteins/chemistry*; Mitochondrial Proteins/metabolism; Molecular Structure; Mutation; Thymidine/analogs & derivatives*; Thymidine/chemistry; Thymidine/genetics; Thymidine/metabolism; Transcription Factors/chemistry*; Transcription Factors/metabolism

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