BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells
Open accessPublished version of a preprint
Abstract
Long interspersed element-1 (LINE-1, or L1) is the only autonomous retrotransposon that is active in human cells. Different host factors have been shown to influence L1 mobility; however, systematic analyses of these factors are limited. Here, we developed a high-throughput microscopy-based retrotransposition assay that identified the double-stranded break (DSB) repair and Fanconi anemia (FA) factors active in the S/G2 phase as potent inhibitors and regulators of L1 activity. In particular, BRCA1, an E3 ubiquitin ligase with a key role in several DNA repair pathways, directly affects L1 retrotransposition frequency and structure and plays a distinct role in controlling L1 ORF2 protein translation through L1 mRNA binding. These results suggest the existence of a 'battleground' at the DNA replication fork between homologous recombination (HR) factors and L1 retrotransposons and reveal a potential role for L1 in the genotypic evolution of tumors characterized by BRCA1 and HR repair deficiencies.
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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 [20]
The Results section on target-site deletions reports DNA nicking and deletions during LINE-1 retrotransposition, supporting the broader point that it can produce DNA lesions. The Discussion section on replication forks also says LINE-1 may create stalled forks through endonuclease-mediated nicking. Our copy does not itself establish that the collateral lesions are specifically double-strand breaks; that point appears in the title of a work listed in the References. (LLM, conf=0.82)
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References 95 · Cited by 113
- Authors
- Mita, P., Sun, X., Fenyö, D., Kahler, D. J., Li, D., Agmon, N., Wudzinska, A., Keegan, S., Bader, J. S., Yun, C., & Boeke, J. D.
- Affiliations
- NYU Langone Health (US)
- Johns Hopkins University (US)
- Corresponding author
- Mita, Paolo
- Boeke, Jef D.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2020-02
- Volume
- 27
- Issue
- 2
- Pages
- 179-191
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC7082080
- OpenAlex
- W3005417928
- Cited by
- 113
- References
- 95
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 16 · 2023: 19 · 2022: 17 · 2021: 16 · 2020: 11
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- New York State Stem Cell Science (Contract C026719, C026719)
- National Institutes of Health (P30CA16087)
- National Institute on Aging (P01AG051449)
- National Cancer Institute (NIH/NCI P30CA16087, P30CA 16087)
- National Institute of General Medical Sciences (P50GM107632)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- LINE-1 retrotransposition, BRCA1, Fanconi anemia pathway, homologous recombination, replication fork, DNA double-strand break repair, siRNA screen
- MeSH terms
- Cell Line, DNA Repair, Fanconi Anemia, HeLa Cells, Humans, Microscopy, S Phase, Gene Deletion, BRCA1 Protein, Long Interspersed Nucleotide Elements, DNA Breaks, Double-Stranded, HEK293 Cells, Homologous Recombination, CRISPR-Cas Systems
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