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

Nat Struct Mol Biol. 2020 Feb;27(2):168-178. doi: 10.1038/s41594-020-0372-1. Epub 2020 Feb 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • DNA / genetics*
  • DNA Replication
  • G1 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Long Interspersed Nucleotide Elements*
  • Neoplasms / genetics*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • DNA