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

Wilson McKerrow, Xuya Wang, Carlos Mendez-Dorantes, Paolo Mita, Song Cao, Mark Grivainis, Li Ding, John LaCava, Kathleen H. Burns, Jef D. Boeke, David Fenyö

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish (US)
    Article numbere2115999119
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume119
    Issue number8
    DOIs
    StatePublished - Feb 22 2022

    Keywords

    • Cancer
    • Copy number alteration
    • DNA damage response
    • LINE-1
    • Retrotransposon
    • Cell Cycle/genetics
    • Long Interspersed Nucleotide Elements/genetics
    • Retroelements/genetics
    • Humans
    • Cell Cycle Proteins/metabolism
    • Databases, Genetic
    • Tumor Suppressor Protein p53/genetics
    • DNA Repair/genetics
    • DNA Breaks, Double-Stranded
    • DNA-Binding Proteins/metabolism
    • Neoplasms/genetics
    • Proteins/genetics
    • Nuclear Proteins/metabolism
    • S Phase Cell Cycle Checkpoints/genetics
    • Gene Expression Regulation, Neoplastic/genetics
    • DNA Copy Number Variations/genetics
    • Gene Expression/genetics

    ASJC Scopus subject areas

    • General

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