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


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.

SUBMITTER: Mita P 

PROVIDER: S-EPMC7082080 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Mita Paolo P   Sun Xiaoji X   Fenyö David D   Kahler David J DJ   Li Donghui D   Agmon Neta N   Wudzinska Aleksandra A   Keegan Sarah S   Bader Joel S JS   Yun Chi C   Boeke Jef D JD  

Nature structural & molecular biology 20200210 2


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, BRCA  ...[more]

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