BRCA1 and S Phase DNA Repair Pathways Restrict LINE-1 Retrotransposition in Human Cells

Long interspersed element-1 (LINE-1 or L1) is the only autonomous retrotransposon 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 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 also 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 HR factors and L1 retrotransposons, and revealing a potential role for L1 in the genotypic evolution of tumors characterized by BRCA1 and HR repair deficiencies.