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

doi:10.1038/s41594-020-0372-1

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.

Authors

Daniel Ardeljan^{1

2

3}, Jared P Steranka⁴, Chunhong Liu⁴, Zhi Li⁵, Martin S Taylor⁶, Lindsay M Payer⁴, Mikhail Gorbounov⁴, Jacob S Sarnecki⁷, Vikram Deshpande⁶, Ralph H Hruban⁴, Jef D Boeke⁵, David Fenyö⁵, Pei-Hsun Wu^{8

9}, Agata Smogorzewska¹⁰, Andrew J Holland¹¹, Kathleen H Burns^{12

13

14}

Affiliations

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.

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

Substances

TP53 protein, human
Tumor Suppressor Protein p53
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding