Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication
Open accessAbstract
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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DNA lesions, in particular dsDNA breaks, can arise as collateral damage associated with retrotransposition.
“DNA lesions, in particular dsDNA breaks (DSB), can arise as ‘collateral damage’ associated with retrotransposition19, 20, 102.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [19]
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References 89 · Cited by 135
- Authors
- 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.
- Affiliations
- Johns Hopkins University (US)
- NYU Langone Health (US)
- Massachusetts General Hospital (US)
- Rockefeller University (US)
- Corresponding author
- Ardeljan, Daniel
- Burns, Kathleen H.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2020-02
- Volume
- 27
- Issue
- 2
- Pages
- 168-178
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC7080318
- OpenAlex
- W3004660847
- Cited by
- 135
- References
- 89
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 21 · 2023: 22 · 2022: 18 · 2021: 20 · 2020: 9 · 2019: 1
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG051449)
- National Cancer Institute (T32CA130840, U54CA210173, F30CA221175, T32CA009110, T32CA193145, T32CA153952)
- National Institute of General Medical Sciences (R01GM130680, R01GM133897, R01GM114119, P50GM107632)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- LINE-1 retrotransposons, retrotransposition, DNA replication, colorectal cancer, TP53, interferon signaling, replication stress, replication fork restart, Fanconi anemia pathway, cell growth
- MeSH terms
- DNA, DNA Replication, HeLa Cells, Humans, Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Long Interspersed Nucleotide Elements, Cell Line, Tumor, Cell Proliferation, HEK293 Cells, G1 Phase Cell Cycle Checkpoints
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