@article{2793e8ca4b9d4dbe9d4b63809e25e2bb,
title = "Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication",
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.}",
note = "Funding Information: Human Brunello CRISPR knockout pooled library was a gift from D. Root and J. Doench (Addgene no. 73178). pSBtet-RN and pSBtet-GN were gifts from E. Kowarz (Addgene plasmid no. 60501 and 60503). pCMV(CAT)T7-SB100 was a gift from Z. Izsvak (Addgene plasmid no, 34879). JM111 was a gift from H. Kazazian. pSicoR-mCh_empty was a gift from M. Ramalho-Santos (Addgene no. 219070). LentiGuide-Puro was a gift from F. Zhang (Addgene no. 52963). We thank J. Gucwa at the Sidney Kimmel Flow Cytometry Core and the staff of the NYU Genome Technology center. We thank J. S. Bader for his statistical expertise. We thank B. A. Bari, R. M. Hughes, B. Vogelstein, J. V. Moran and H. H. Kazazian for helpful discussion and review of the manuscript. We thank J. Fairman of the Department of Art as Applied to Medicine at Johns Hopkins University School of Medicine for illustrations. This study was funded by F30CA221175 (D.A.), P50GM107632 (K.H.B., J.D.B., D.F.), U54CA210173 (P.W.) and the Sol Goldman Pancreatic Research Center (K.H.B., R.H.H.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = feb,
day = "1",
doi = "10.1038/s41594-020-0372-1",
language = "English (US)",
volume = "27",
pages = "168--178",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "2",
}