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

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

Biomedical Engineering

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	168-178
Number of pages	11
Journal	Nature Structural and Molecular Biology
Volume	27
Issue number	2
DOIs	https://doi.org/10.1038/s41594-020-0372-1
State	Published - Feb 1 2020

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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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

Ardeljan, D, Steranka, JP, Liu, C, Li, Z, Taylor, MS, Payer, LM, Gorbounov, M, Sarnecki, JS, Deshpande, V, Hruban, RH, Boeke, JD, Fenyö, D, Wu, PH, Smogorzewska, A, Holland, AJ & Burns, KH 2020, 'Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication', Nature Structural and Molecular Biology, vol. 27, no. 2, pp. 168-178. https://doi.org/10.1038/s41594-020-0372-1

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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.",

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

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AU - Ardeljan, Daniel

AU - Steranka, Jared P.

AU - Liu, Chunhong

AU - Li, Zhi

AU - Taylor, Martin S.

AU - Payer, Lindsay M.

AU - Gorbounov, Mikhail

AU - Sarnecki, Jacob S.

AU - Deshpande, Vikram

AU - Hruban, Ralph H.

AU - Boeke, Jef D.

AU - Fenyö, David

AU - Wu, Pei Hsun

AU - Smogorzewska, Agata

AU - Holland, Andrew J.

AU - Burns, Kathleen H.

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AB - 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.

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

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