期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 2, 页码 179-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-020-0374-z
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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. Whole-genome siRNA screens to identify regulators of human LINE-1 retrotransposition reveal that BRCA1 and Fanconi anemia DNA repair factors inhibit retrotransposition at stalled replication fork targets created and exploited by L1.
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