Institute for Systems Genetics, New York University Grossman School of Medicine, New York, NY 10016.
Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016.
Proc Natl Acad Sci U S A. 2022 Feb 22;119(8). doi: 10.1073/pnas.2115999119.
Retrotransposons are genomic DNA sequences that copy themselves to new genomic locations via RNA intermediates; LINE-1 is the only active and autonomous retrotransposon in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues but is derepressed in many cancers, where LINE-1 retrotransposition is correlated with p53 mutation and copy number alteration (CNA). In cell lines, inducing LINE-1 expression can cause double-strand breaks (DSBs) and replication stress. Reanalyzing multiomic data from breast, ovarian, endometrial, and colon cancers, we confirmed correlations between LINE-1 expression, p53 mutation status, and CNA. We observed a consistent correlation between LINE-1 expression and the abundance of DNA replication complex components, indicating that LINE-1 may also induce replication stress in human tumors. In endometrial cancer, high-quality phosphoproteomic data allowed us to identify the DSB-induced ATM-MRN-SMC S phase checkpoint pathway as the primary DNA damage response (DDR) pathway associated with LINE-1 expression. Induction of LINE-1 expression in an in vitro model led to increased phosphorylation of MRN complex member RAD50, suggesting that LINE-1 directly activates this pathway.
逆转录转座子是通过 RNA 中间体将自身复制到新基因组位置的基因组 DNA 序列；LINE-1 是人类基因组中唯一活跃且自主的逆转录转座子。LINE-1 的移动性在体细胞组织中受到很大抑制，但在许多癌症中被解除抑制，在这些癌症中，LINE-1 逆转录转位与 p53 突变和拷贝数改变（CNA）相关。在细胞系中，诱导 LINE-1 表达会导致双链断裂（DSB）和复制应激。我们重新分析了来自乳腺癌、卵巢癌、子宫内膜癌和结肠癌的多组学数据，证实了 LINE-1 表达、p53 突变状态和 CNA 之间的相关性。我们观察到 LINE-1 表达与 DNA 复制复合物成分的丰度之间存在一致的相关性，表明 LINE-1 也可能在人类肿瘤中诱导复制应激。在子宫内膜癌中，高质量的磷酸化蛋白质组学数据使我们能够鉴定出 DSB 诱导的 ATM-MRN-SMC S 期检查点途径作为与 LINE-1 表达相关的主要 DNA 损伤反应（DDR）途径。在体外模型中诱导 LINE-1 表达会导致 MRN 复合物成员 RAD50 的磷酸化增加，这表明 LINE-1 直接激活了该途径。
