TY - JOUR
T1 - BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells
AU - Mita, Paolo
AU - Sun, Xiaoji
AU - Fenyö, David
AU - Kahler, David J.
AU - Li, Donghui
AU - Agmon, Neta
AU - Wudzinska, Aleksandra
AU - Keegan, Sarah
AU - Bader, Joel S.
AU - Yun, Chi
AU - Boeke, Jef D.
N1 - Funding Information:
We thank T. Huang and K. H. Burns for helpful discussions and comments on the manuscript. This work was supported by NIH grants P50GM107632 to J.D.B. and P01AG051449 to J. Sedivy.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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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U2 - 10.1038/s41594-020-0374-z
DO - 10.1038/s41594-020-0374-z
M3 - Article
C2 - 32042152
AN - SCOPUS:85079237411
SN - 1545-9993
VL - 27
SP - 179
EP - 191
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -