A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3, N[superscript4]-ethenocytosine

• Main Authors: Iyama, Teruaki (Author), Chaim, Isaac Alexander (Contributor), Gardner, Alycia M. (Contributor), Wu, Jie (Contributor), Wilson, David M. (Contributor), Samson, Leona D (Contributor)
• Other Authors: Massachusetts Institute of Technology. Center for Environmental Health Sciences (Contributor), Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Oxford University Press, 2017-06-21T16:06:33Z.
• Subjects: Article
• Online Access: Get fulltext

Etheno (ε) 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 ε-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,N4-ethenocytosine (εC) 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 εC. 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 εC from the genome, and thus in the protection of cells and tissues from collateral damage induced by inflammatory responses.
National Institutes of Health (U.S.) (Directors Pioneer Award [DPI-ES022576])
National Institutes of Health (U.S.) (R01-CA075576)
National Institutes of Health (U.S.) (R01-CA55042)
National Institutes of Health (U.S.) (R01-CA149261)
National Institutes of Health (U.S.) (P30-ES02109)
National Institutes of Health (U.S.). Intramural Research Program
National Institute on Aging
LDS discretionary funds