title: Nucleotide excision repair deficiency increases levels of acrolein-derived cyclic DNA adduct and sensitizes cells to apoptosis induced by docosahexaenoic acid and acrolein.
abstract: The acrolein derived cyclic 1,N(2)-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Jishen
authors.initials: J
authors.lastname: Pan
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Marcin
authors.initials: M
authors.lastname: Dyba
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Supti
authors.initials: S
authors.lastname: Sen
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Berry
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Creswell
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States.
authors.forename: Rabindra
authors.initials: R
authors.lastname: Roy
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States. Electronic address: flc6@georgetown.edu.
authors.forename: Fung-Lung
authors.initials: FL
authors.lastname: Chung
mesh_terms: D000171:Acrolein / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000633:toxicity; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics
chemical_list: D018736:DNA Adducts; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C559361:cyclic 1,N2-propanoguanosine; D006151:Guanosine; D004281:Docosahexaenoic Acids; D000171:Acrolein
keywords: Acrolein; Apoptosis; DNA adduct; Docosahexaenoic acid; Nucleotide excision repair