A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3, N-4-ethenocytosine

作者：Chaim Isaac A; Gardner Alycia; Wu Jie; Iyama Teruaki; Wilson David M III; Samson Leona D^*

来源：Nucleic Acids Research, 2017, 45(6): 3242-3252.

DOI：10.1093/nar/gkx015

Etheno (epsilon) DNA base adducts are highly mutagenic lesions produced endogenously via reactions with lipid peroxidation (LPO) products. Cancer-promoting conditions, such as inflammation, can induce persistent oxidative stress and increased LPO, resulting in the accumulation of epsilon-adducts in different tissues. Using a recently described fluorescence multiplexed host cell reactivation assay, we show that a plasmid reporter bearing a site-specific 3, N-4-ethenocytosine (epsilon C) causes transcriptional blockage. Notably, this blockage is exacerbated in Cockayne Syndrome and xeroderma pigmentosum patient-derived lymphoblastoid and fibroblast cells. Parallel RNA-Seq expression analysis of the plasmid reporter identifies novel transcriptional mutagenesis properties of epsilon C. Our studies reveal that beyond the known pathways, such as base excision repair, the process of transcription-coupled nucleotide excision repair plays a role in the removal of epsilon C from the genome, and thus in the protection of cells and tissues from collateral damage induced by inflammatory responses.

• 出版日期2017-4-7
• 单位MIT; NIH