《Nature》:拒绝酒精,远离癌症!

剑桥大学MRC分子生物学实验室于昨日在著名医学杂志《Nature》发表论文《Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells》,证实了酒精会对体内的干细胞造成不可逆转的基因损伤。并且科学家表示,在血细胞中观察到的酒精产生的影响也适用于人体其他细胞。


以往多项研究就表明饮酒可以提升患癌症的风险, 特别是口腔癌、食道癌、肠癌、喉癌等的风险。探明了酒精的代谢产物乙醛是‘罪魁祸首’,而关于乙醛在人体内的‘行凶过程’尚不清楚。


人体内防止乙醛破坏的途径主要有两种,首先是乙醛脱氢酶(ALDH2),它的作用是将乙醛分解为乙酸,以防止乙醛在体内的积累,但遗憾的是,全球约5.4亿的人携带Aldh2基因突变,不能正常编码ALDH2蛋白,因而不能分解乙醛,常出现酒后脸红、心跳加速等症状,这也是食道癌发生的主要原因。


另外一种途径是人体内的DNA修复系统,其中一个重要的成员就是FANCD2,是一种DNA交联修复蛋白,缺陷时会导致遗传性疾病Fanconi贫血,(一种导致异常发育,骨髓衰竭和癌症的破坏性病症)有些人携带有Fancd2基因突变,无法修复由乙醛对DNA的破坏,进而产生永久性的损伤,引发癌症。


本研究中,研究者利用转基因技术敲除小鼠的Aldh2基因和Fancd2基因,破坏小鼠抵抗乙醛损害的 ‘两道屏障’,随后,对基因敲除后小鼠进行为期10天的低度酒精腹腔注射,研究结果发现,这些摄入酒精后的基因敲除小鼠完全丧失了造血的功能。同时,对这些小鼠进行了基因组测序,结果表明细胞内DNA不稳定性猛增。

本研究对于揭示酒精与癌症风险之间的联系具有重要的意义,众多的酒精爱好者也敲响了警钟:拒绝酒精,远离癌症!

Abstract

Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair. Moreover, deletion of p53 completely rescues the survival of aldehyde-stressed and mutated haematopoietic stem cells, but does not change the pattern or the intensity of genome instability within individual stem cells. These findings characterize the mutation of the stem-cell genome by an alcohol-derived and endogenous source of DNA damage. Furthermore, we identify how the choice of DNA-repair pathway and a stringent p53 response limit the transmission of aldehyde-induced mutations in stem cells.


Methods

• SCE assay for mouse bone marrow

• M-FISH karyotyping

• DT40 clonogenic survival

• Sensitivity assays of primary mouse B cells

• Survival assays of colony-forming units (CFU)

• Flow cytometry

• Blood counts

• Western blot

• Histological analysis

• In vivo point mutation assay


Results

• Ethanol stimulates homologous recombination repair

• FANCD2 prevents alcohol-induced genomic instability

• Ku70 contributes to repair of aldehyde-induced DSBs

• Aldehyde-damaged HSCs are functionally compromised

• Mutational landscape of aldehyde-damaged stem cells

• A p53 response removes aldehyde-damaged HSCs


Reference

https://www.nature.com/articles/nature25154



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