期刊
TOXICOLOGICAL SCIENCES
卷 169, 期 1, 页码 235-245出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfz037
关键词
acetaldehyde; ethanol; OVCA2; CRISPR screening; DNA repair
类别
资金
- Superfund Hazardous Substance Research and Training Program [P42ES004705]
- University of Florida, Gainesville
Acetaldehyde, a metabolite of ethanol, is a cellular toxicant and a human carcinogen. A genome-wide CRISPR-based loss-of-function screen in erythroleukemic K562 cells revealed candidate genetic contributors affecting acetaldehyde cytotoxicity. Secondary screening exposing cells to a lower acetaldehyde dose simultaneously validated multiple candidate genes whose loss results in increased sensitivity to acetaldehyde. Disruption of genes encoding components of various DNA repair pathways increased cellular sensitivity to acetaldehyde. Unexpectedly, the tumor suppressor gene OVCA2, whose function is unknown, was identified in our screen as a determinant of acetaldehyde tolerance. Disruption of the OVCA2 gene resulted in increased acetaldehyde sensitivity and higher accumulation of the acetaldehyde-derived DNA adduct N-2-ethylidene-dG. Together these results are consistent with a role for OVCA2 in adduct removal and/or DNA repair.
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