赖以生存的工具：细菌 DNA 结构阐明癌症。
Tools To Live By: Bacterial DNA Structures Illuminate Cancer.
机构信息
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX 77030, USA.
出版信息
Trends Genet. 2019 May;35(5):383-395. doi: 10.1016/j.tig.2019.03.001. Epub 2019 Apr 5.
Holliday junctions (HJs) are DNA intermediates in homology-directed DNA repair and replication stalling, but until recently were undetectable in living cells. We review how an engineered protein that traps and labels HJs in Escherichia coli illuminates the biology of DNA and cancer. HJ chromatin immunoprecipitation with deep sequencing (ChIP-seq) analysis showed the directionality of double-strand break (DSB) repair in the E. coli genome. Quantification of HJs as fluorescent foci in live cells revealed that the commonest spontaneous problem repaired via HJs is replication-dependent single-stranded DNA gaps, not DSBs. Focus quantification also indicates that RecQ DNA helicase plays dual roles in promoting repair HJs and preventing replication-stall HJs in an E. coli model of RAD51-overexpressing (most) cancers. Moreover, cancer transcriptomes imply that most cancers suffer frequent fork stalls that are reduced by the HJ removers EME1 and GEN1, as well as by the human RecQ orthologs BLM and RECQL4-surprising potential procancer roles for these known cancer-preventing proteins.
霍利迪连接点（HJs）是同源定向 DNA 修复和复制停滞过程中的 DNA 中间体，但直到最近才在活细胞中被检测到。我们回顾了一种在大肠杆菌中捕获和标记 HJs 的工程蛋白如何阐明 DNA 和癌症的生物学。HJs 的染色质免疫沉淀与深度测序（ChIP-seq）分析显示了大肠杆菌基因组中双链断裂（DSB）修复的方向性。通过活细胞中荧光焦点的定量分析表明，通过 HJs 修复的最常见的自发性问题是复制依赖性单链 DNA 缺口，而不是 DSBs。焦点定量分析还表明，RecQ DNA 解旋酶在 RAD51 过表达（大多数）癌症的大肠杆菌模型中，在促进修复 HJs 和防止复制停滞 HJs 方面发挥双重作用。此外，癌症转录组表明，大多数癌症经常发生叉状停顿，而 HJ 去除酶 EME1 和 GEN1 以及人类 RecQ 同源物 BLM 和 RECQL4 可以减少这种停顿，这为这些已知的预防癌症蛋白提供了潜在的促癌作用。
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