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Nat Struct Mol Biol. 2020 Feb;27(2):179-191. doi: 10.1038/s41594-020-0374-z. Epub 2020 Feb 10.

BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells.

Author information

1
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, USA. Paolo.Mita@nyulangone.org.
2
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, USA.
3
Cellarity Inc., Cambridge, MA, USA.
4
High Throughput Biology Core, NYU Langone Health, New York, NY, USA.
5
Planet Pharma, Boston, MA, USA.
6
Flagship VL58, Inc., Cambridge, MA, USA.
7
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
8
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, USA. Jef.Boeke@nyulangone.org.

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.

PMID:
32042152
PMCID:
PMC7082080
[Available on 2020-08-10]
DOI:
10.1038/s41594-020-0374-z

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