Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication

Daniel Ardeljan, Jared P. Steranka, Chunhong Liu, Zhi Li, Martin S. Taylor, Lindsay M. Payer, Mikhail Gorbounov, Jacob S. Sarnecki, Vikram Deshpande, Ralph H. Hruban, Jef D. Boeke, David Fenyö, Pei Hsun Wu, Agata Smogorzewska, Andrew J. Holland, Kathleen H. Burns

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)168-178
    Number of pages11
    JournalNature Structural and Molecular Biology
    Volume27
    Issue number2
    DOIs
    StatePublished - Feb 1 2020

    ASJC Scopus subject areas

    • Structural Biology
    • Molecular Biology

    Fingerprint Dive into the research topics of 'Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication'. Together they form a unique fingerprint.

    Cite this