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

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

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
2
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
3
Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
4
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA.
6
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
7
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
8
Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, MD, USA.
9
Institute for NanoBiotechnology, Johns Hopkins University, Baltimore, MD, USA.
10
Laboratory of Genome Maintenance, The Rockefeller University, New York City, NY, USA.
11
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
12
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kburns@jhmi.edu.
13
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kburns@jhmi.edu.
14
Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kburns@jhmi.edu.

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.

PMID:
32042151
PMCID:
PMC7080318
[Available on 2020-08-10]
DOI:
10.1038/s41594-020-0372-1

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