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 journalArticle

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

    Fingerprint

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Ardeljan, D., Steranka, J. P., Liu, C., Li, Z., Taylor, M. S., Payer, L. M., Gorbounov, M., Sarnecki, J. S., Deshpande, V., Hruban, R. H., Boeke, J. D., Fenyö, D., Wu, P. H., Smogorzewska, A., Holland, A. J., & Burns, K. H. (2020). Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication. Nature Structural and Molecular Biology, 27(2), 168-178. https://doi.org/10.1038/s41594-020-0372-1