• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

酒精和内源性醛会损伤染色体并使干细胞发生突变。

Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells.

机构信息

MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.

Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

出版信息

Nature. 2018 Jan 11;553(7687):171-177. doi: 10.1038/nature25154. Epub 2018 Jan 3.

DOI:10.1038/nature25154
PMID:29323295
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6047743/
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.

摘要

造血干细胞更新血液。这些细胞中 DNA 损伤的积累会促进其衰退，而损伤的错误修复则会引发恶性肿瘤。在这里，我们描述了内源性和酒精衍生代谢物乙醛引起的 DNA 损伤的特征和突变特征。这种损伤会导致 DNA 双链断裂，尽管会刺激重组修复，但也会导致染色体重排。我们将单个造血干细胞的移植与全基因组测序相结合，表明这种损伤发生在干细胞中，导致微同源介导的末端连接修复的缺失和重排。此外，p53 的缺失完全挽救了应激和突变的造血干细胞的存活，但不会改变单个干细胞内基因组不稳定性的模式或强度。这些发现描述了由酒精衍生和内源性 DNA 损伤源引起的干细胞基因组突变。此外，我们确定了 DNA 修复途径的选择和严格的 p53 反应如何限制在干细胞中传递乙醛诱导的突变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/685eff1c4a39/emss-78399-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/5c6c9a99dc97/emss-78399-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/104694266695/emss-78399-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/8d7277c1580b/emss-78399-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/28aee6e42df6/emss-78399-f010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a5f8e58b5f24/emss-78399-f011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/895ea7965a1e/emss-78399-f012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a48f184eaf2a/emss-78399-f013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/f5b6dbb42578/emss-78399-f014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a3414ceecefa/emss-78399-f015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/47d85036308f/emss-78399-f016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/18784c339240/emss-78399-f017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/6d3aa651ee7f/emss-78399-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/8d51a1c6faa2/emss-78399-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/bb8ff307535f/emss-78399-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/f785cb99f4ae/emss-78399-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/3761a91e7bb5/emss-78399-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/685eff1c4a39/emss-78399-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/5c6c9a99dc97/emss-78399-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/104694266695/emss-78399-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/8d7277c1580b/emss-78399-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/28aee6e42df6/emss-78399-f010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a5f8e58b5f24/emss-78399-f011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/895ea7965a1e/emss-78399-f012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a48f184eaf2a/emss-78399-f013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/f5b6dbb42578/emss-78399-f014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/a3414ceecefa/emss-78399-f015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/47d85036308f/emss-78399-f016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/18784c339240/emss-78399-f017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/6d3aa651ee7f/emss-78399-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/8d51a1c6faa2/emss-78399-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/bb8ff307535f/emss-78399-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/f785cb99f4ae/emss-78399-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/3761a91e7bb5/emss-78399-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1253/6047743/685eff1c4a39/emss-78399-f006.jpg

相似文献

1
Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells.酒精和内源性醛会损伤染色体并使干细胞发生突变。
Nature. 2018 Jan 11;553(7687):171-177. doi: 10.1038/nature25154. Epub 2018 Jan 3.
2
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.内源性醛类对小鼠造血干细胞功能的遗传毒性后果。
Nature. 2012 Sep 27;489(7417):571-5. doi: 10.1038/nature11368. Epub 2012 Aug 26.
3
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.Fancd2 可拮抗小鼠体内天然产生的醛类的毒性作用。
Nature. 2011 Jul 6;475(7354):53-8. doi: 10.1038/nature10192.
4
Metabolism: alcohol, DNA and disease.代谢：酒精、DNA与疾病。
Nature. 2011 Jul 6;475(7354):45-6. doi: 10.1038/475045a.
5
Compromised repair of radiation-induced DNA double-strand breaks in Fanconi anemia fibroblasts in G2.G2 期范可尼贫血成纤维细胞中辐射诱导的 DNA 双链断裂修复受损。
DNA Repair (Amst). 2020 Dec;96:102992. doi: 10.1016/j.dnarep.2020.102992. Epub 2020 Oct 6.
6
p53-TP53-Induced Glycolysis Regulator Mediated Glycolytic Suppression Attenuates DNA Damage and Genomic Instability in Fanconi Anemia Hematopoietic Stem Cells.p53-TP53 诱导的糖酵解调节因子介导的糖酵解抑制可减轻范可尼贫血造血干细胞中的 DNA 损伤和基因组不稳定性。
Stem Cells. 2019 Jul;37(7):937-947. doi: 10.1002/stem.3015. Epub 2019 May 3.
7
NHEJ-Mediated Repair of CRISPR-Cas9-Induced DNA Breaks Efficiently Corrects Mutations in HSPCs from Patients with Fanconi Anemia.NHEJ 介导的 CRISPR-Cas9 诱导的 DNA 断裂修复可有效纠正范可尼贫血患者造血干细胞中的突变。
Cell Stem Cell. 2019 Nov 7;25(5):607-621.e7. doi: 10.1016/j.stem.2019.08.016. Epub 2019 Sep 19.
8
Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg.与 Fancg 缺乏导致的范可尼贫血相比，Fancd2 缺乏导致的小鼠基因组不稳定性更大。
Cancer Res. 2010 Dec 1;70(23):9703-10. doi: 10.1158/0008-5472.CAN-09-1022. Epub 2010 Nov 30.
9
Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.范可尼贫血症的骨髓衰竭是由过度的 p53/p21 DNA 损伤反应引发的，该反应会损害造血干细胞和祖细胞。
Cell Stem Cell. 2012 Jul 6;11(1):36-49. doi: 10.1016/j.stem.2012.05.013. Epub 2012 Jun 7.
10
FANCD2 limits acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes.FANCD2 限制食管角质细胞在 DNA 复制过程中乙醛诱导的基因组不稳定性。
Mol Oncol. 2021 Nov;15(11):3109-3124. doi: 10.1002/1878-0261.13072. Epub 2021 Aug 8.

引用本文的文献

1
Mechanisms of human germ cell development.人类生殖细胞发育的机制。
Nat Rev Mol Cell Biol. 2025 Sep 16. doi: 10.1038/s41580-025-00893-6.
2
Integrating genomic and pathological characteristics to enhance prognostic precision in advanced NSCLC.整合基因组和病理特征以提高晚期非小细胞肺癌的预后精准度。
NPJ Precis Oncol. 2025 Aug 2;9(1):271. doi: 10.1038/s41698-025-01056-8.
3
MDM4 overexpression alleviates developmental and hematopoietic defects in Fancg deficient mice.MDM4过表达可减轻Fancg缺陷小鼠的发育和造血缺陷。

本文引用的文献

1
A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability.一类环境毒素和内源性毒素可导致BRCA2单倍体不足及基因组不稳定。
Cell. 2017 Jun 1;169(6):1105-1118.e15. doi: 10.1016/j.cell.2017.05.010.
2
Essential Roles for Polymerase θ-Mediated End Joining in the Repair of Chromosome Breaks.聚合酶θ介导的末端连接在染色体断裂修复中的重要作用
Mol Cell. 2016 Aug 18;63(4):662-673. doi: 10.1016/j.molcel.2016.06.020. Epub 2016 Jul 21.
3
p53 downregulates the Fanconi anaemia DNA repair pathway.p53下调范可尼贫血DNA修复途径。
Leukemia. 2025 Jul 25. doi: 10.1038/s41375-025-02692-6.
4
ALDH9A1 deficiency as a source of endogenous DNA damage that requires repair by the Fanconi anemia pathway.乙醛脱氢酶9A1缺乏作为内源性DNA损伤的一个来源，这种损伤需要通过范可尼贫血途径进行修复。
J Cell Biol. 2025 Jul 7;224(7). doi: 10.1083/jcb.202407141. Epub 2025 Jun 20.
5
The risk factors, pathogenesis and treatment of premature ovarian insufficiency.卵巢早衰的危险因素、发病机制及治疗
J Ovarian Res. 2025 Jun 18;18(1):134. doi: 10.1186/s13048-025-01714-2.
6
Whether aristolochic acid directly drives hepatocarcinogenesis: comprehensive investigations from mutational signatures to animal models.马兜铃酸是否直接驱动肝癌发生：从突变特征到动物模型的全面研究
Arch Toxicol. 2025 May 30. doi: 10.1007/s00204-025-04087-z.
7
Loss of Heterozygosity associated with ubiquitous environments in yeast.酵母中与普遍存在的环境相关的杂合性缺失。
PLoS Genet. 2025 May 12;21(5):e1011692. doi: 10.1371/journal.pgen.1011692. eCollection 2025 May.
8
Ferumoxytol promotes haematopoietic stem cell post-injury regeneration as a reactive oxygen species scavenger.铁羧麦芽糖作为一种活性氧清除剂，可促进造血干细胞损伤后的再生。
Nat Nanotechnol. 2025 Apr 23. doi: 10.1038/s41565-025-01907-2.
9
Smoking, alcohol and risk of sarcopenia: a Mendelian randomisation study.吸烟、饮酒与肌肉减少症风险：一项孟德尔随机化研究。
BMJ Open. 2025 Apr 7;15(4):e091656. doi: 10.1136/bmjopen-2024-091656.
10
Transcription blocking properties and transcription-coupled repair of N-alkylguanine adducts as a model for aldehyde-induced DNA damage.作为醛诱导DNA损伤模型的N-烷基鸟嘌呤加合物的转录阻断特性和转录偶联修复
J Biol Chem. 2025 Mar 27;301(5):108459. doi: 10.1016/j.jbc.2025.108459.
Nat Commun. 2016 Apr 1;7:11091. doi: 10.1038/ncomms11091.
4
The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription.范可尼贫血通路通过协调复制和转录来维持基因组稳定性。
Mol Cell. 2015 Nov 5;60(3):351-61. doi: 10.1016/j.molcel.2015.09.012. Epub 2015 Oct 22.
5
The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.范可尼贫血通路保护基因组完整性免受R环影响。
PLoS Genet. 2015 Nov 19;11(11):e1005674. doi: 10.1371/journal.pgen.1005674. eCollection 2015 Nov.
6
The genome as a record of environmental exposure.作为环境暴露记录的基因组。
Mutagenesis. 2015 Nov;30(6):763-70. doi: 10.1093/mutage/gev073. Epub 2015 Oct 6.
7
Alcohol as a risk factor for cancer: existing evidence in a global perspective.酒精作为癌症的一个风险因素：全球视角下的现有证据。
J Prev Med Public Health. 2015 Jan;48(1):1-9. doi: 10.3961/jpmph.14.052. Epub 2015 Jan 27.
8
Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia.醛脱氢酶-2基因多态性与儿童特发性再生障碍性贫血骨髓衰竭的进展有关。
Br J Haematol. 2015 Feb;168(3):460-3. doi: 10.1111/bjh.13122. Epub 2014 Sep 11.
9
Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining.人类细胞中的染色体易位是由规范的非同源末端连接产生的。
Mol Cell. 2014 Sep 18;55(6):829-842. doi: 10.1016/j.molcel.2014.08.002. Epub 2014 Sep 4.
10
Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis.通过整合蛋白质组、转录组和 DNA 甲基化组分析鉴定造血干细胞及其早期祖细胞中的调控网络。
Cell Stem Cell. 2014 Oct 2;15(4):507-522. doi: 10.1016/j.stem.2014.07.005. Epub 2014 Aug 21.