title: A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3,N4-ethenocytosine.
abstract: 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.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Isaac A
authors.initials: IA
authors.lastname: Chaim
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Alycia
authors.initials: A
authors.lastname: Gardner
authors.affiliation: The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility in the Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Iyama
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D014983:Xeroderma Pigmentosum / Q000235:genetics
chemical_list: C018289:3,N(4)-ethenocytosine; D018736:DNA Adducts; C004981:1,N(6)-ethenoadenine; D003596:Cytosine; D012319:RNA Polymerase II; D045643:DNA Repair Enzymes; D000225:Adenine