异染色质编码卫星 RNA 诱导乳腺癌。
Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer.
机构信息
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
出版信息
Mol Cell. 2018 Jun 7;70(5):842-853.e7. doi: 10.1016/j.molcel.2018.04.023. Epub 2018 May 31.
Heterochromatic repetitive satellite RNAs are extensively transcribed in a variety of human cancers, including BRCA1 mutant breast cancer. Aberrant expression of satellite RNAs in cultured cells induces the DNA damage response, activates cell cycle checkpoints, and causes defects in chromosome segregation. However, the mechanism by which satellite RNA expression leads to genomic instability is not well understood. Here we provide evidence that increased levels of satellite RNAs in mammary glands induce tumor formation in mice. Using mass spectrometry, we further show that genomic instability induced by satellite RNAs occurs through interactions with BRCA1-associated protein networks required for the stabilization of DNA replication forks. Additionally, de-stabilized replication forks likely promote the formation of RNA-DNA hybrids in cells expressing satellite RNAs. These studies lay the foundation for developing novel therapeutic strategies that block the effects of non-coding satellite RNAs in cancer cells.
异染色质重复卫星 RNA 在多种人类癌症中广泛转录，包括 BRCA1 突变型乳腺癌。卫星 RNA 在培养细胞中的异常表达会诱导 DNA 损伤反应，激活细胞周期检查点，并导致染色体分离缺陷。然而，卫星 RNA 表达导致基因组不稳定性的机制尚不清楚。在这里，我们提供的证据表明，乳腺中卫星 RNA 水平的增加会诱导小鼠形成肿瘤。通过质谱分析，我们进一步表明，卫星 RNA 引起的基因组不稳定性是通过与 BRCA1 相关蛋白网络相互作用而发生的，该蛋白网络对于稳定 DNA 复制叉是必需的。此外，不稳定的复制叉可能会促进在表达卫星 RNA 的细胞中 RNA-DNA 杂交的形成。这些研究为开发新型治疗策略奠定了基础，该策略可以阻断非编码卫星 RNA 在癌细胞中的作用。
Zotero 插件