4.8 Article

LINE-1 expression in cancer correlates with p53 mutation, copy number alteration, and S phase checkpoint

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2115999119

Keywords

retrotransposon; LINE-1; cancer; DNA damage response; copy number alteration

Funding

  1. NCI, NIH [HHSN261200800001E]
  2. NIH [P01AG051449, U24CA210972, 1R21CA235521]

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LINE-1, an active retrotransposon, is derepressed in many cancers and is correlated with p53 mutation and copy number alteration. It induces replication stress and is associated with the DNA damage response pathway in endometrial cancer.
Retrotransposons are genomic DNA sequences that copy them-selves 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 expres-sion. 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.

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