Chen Jian, Shukla Vivek, Farci Patrizia, Andricovich Jaclyn, Jogunoori Wilma, Kwong Lawrence N, Katz Lior H, Shetty Kirti, Rashid Asif, Su Xiaoping, White Jon, Li Lei, Wang Alan Yaoqi, Blechacz Boris, Raju Gottumukkala S, Davila Marta, Nguyen Bao-Ngoc, Stroehlein John R, Chen Junjie, Kim Sang Soo, Levin Heather, Machida Keigo, Tsukamoto Hidekazu, Michaely Peter, Tzatsos Alexandros, Mishra Bibhuti, Amdur Richard, Mishra Lopa
Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
Thoracic Oncology Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD.
Hepatology. 2017 Feb;65(2):678-693. doi: 10.1002/hep.28927. Epub 2016 Dec 24.
Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor β/mothers against decapentaplegic homolog 3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of β2SP leads to decreased Fancd2 levels and sensitizes β2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor β stimulation is regulated by the β2SP/mothers against decapentaplegic homolog 3 complex.
Dysfunctional transforming growth factor β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).
暴露于乙醇衍生的乙醛等基因毒素会导致DNA损伤和肝损伤，并促进癌症的发展。我们在此报告转化生长因子β/抗五肢瘫同源物3衔接蛋白β2-血影蛋白（β2SP，基因Sptbn1）在酒精诱导的DNA损伤后维持基因组稳定性方面的重要作用。β2SP通过依赖β2SP激活范可尼贫血互补组D2（Fancd2）来支持DNA修复，Fancd2是范可尼贫血复合物的核心成分。β2SP的缺失导致Fancd2水平降低，并使β2SP突变体对乙醇处理引起的DNA损伤敏感，导致的表型与同时缺乏醛脱氢酶2和Fancd2的动物中观察到的表型非常相似，且类似于人类胎儿酒精综合征。Sptbn1缺陷细胞对DNA交联剂高度敏感，并且具有有缺陷的DNA双链断裂修复，而异位表达Fancd2可挽救这种修复缺陷。此外，Fancd2在响应DNA损伤/转化生长因子β刺激时的转录受β2SP/抗五肢瘫同源物3复合物调控。
功能失调的转化生长因子β/β2SP信号传导通过改变范可尼贫血DNA修复途径影响基因毒性代谢产物的处理。（《肝脏病学》2017年；65：678 - 693）
