期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 2, 页码 168-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-020-0372-1
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资金
- NCI NIH HHS [T32 CA153952, T32 CA009110, F30 CA221175, T32 CA193145, T32 CA130840] Funding Source: Medline
- NIA NIH HHS [P01 AG051449] Funding Source: Medline
- NIGMS NIH HHS [R01 GM130680, R01 GM114119, R01 GM133897, P50 GM107632] Funding Source: Medline
LINE-1 retrotransposon overexpression is a hallmark of human cancers. We identified a colorectal cancer wherein a fast-growing tumor subclone downregulated LINE-1, prompting us to examine how LINE-1 expression affects cell growth. We find that nontransformed cells undergo a TP53-dependent growth arrest and activate interferon signaling in response to LINE-1. TP53 inhibition allows LINE-1(+) cells to grow, and genome-wide-knockout screens show that these cells require replication-coupled DNA-repair pathways, replication-stress signaling and replication-fork restart factors. Our findings demonstrate that LINE-1 expression creates specific molecular vulnerabilities and reveal a retrotransposition-replication conflict that may be an important determinant of cancer growth. Knockout screens to assess the effect of LINE-1 expression on cell growth show that TP53-deficient cells require replication-stress signaling and replication-fork restart factors to suppress LINE-1 toxicity, and that LINE-1 expression activates the Fanconi anemia pathway, suggesting that retrotransposition conflicts with DNA replication.
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