Abstract
Expression of the L1 retrotransposon can damage the genome through insertional mutagenesis and the generation of DNA double-strand breaks (DSBs). The majority of L1 loci in the human genome are 5′-truncated and therefore incapable of retrotransposition. While thousands of full-length L1 loci remain, most are retrotranspositionally-incompetent due to inactivating mutations. However, mutations leading to premature stop codons within the L1 ORF2 sequence may yield truncated proteins that retain a functional endonuclease domain. We demonstrate that some truncated ORF2 proteins cause varying levels of toxicity and DNA damage when chronically overexpressed in mammalian cells. Furthermore, transfection of some ORF2 constructs containing premature stop codons supported low levels of Alu retrotransposition, demonstrating the potential for select retrotranspositionally-incompetent L1 loci to generate genomic instability. This result suggests yet another plausible explanation for the relative success of Alu elements in populating the human genome. Our data suggest that a subset of retrotranspositionally-incompetent L1s, previously considered to be harmless to genomic integrity, may have the potential to cause chronic DNA damage by introducing DSBs and mobilizing Alu. These results imply that the number of known L1 loci in the human genome that potentially threaten its stability may not be limited to the retrotranspositionally active loci.
Highlights
Expression of the Long INterspersed Element-1 (LINE-1 or L1) retrotransposon can compromise genomic integrity through insertional mutagenesis, rearrangements generated by non-allelic homologous recombination and the generation of DNA double-strand breaks (DSBs) [1,2,3,4,5,6]
L1-driven insertional mutagenesis is known to cause a variety of human genetic diseases; much of the current L1-related disease research focuses on the identification and quantification of de novo L1 retrotransposition events [reviewed in [22,56,57]]
It is estimated that 80–100 of the ∼500,000 fixed L1 loci in the human genome are capable of retrotransposition, with only a few highly active L1s responsible for most of the retrotransposition [32,58]
Summary
Expression of the Long INterspersed Element-1 (LINE-1 or L1) retrotransposon can compromise genomic integrity through insertional mutagenesis, rearrangements generated by non-allelic homologous recombination and the generation of DNA double-strand breaks (DSBs) [1,2,3,4,5,6]. L1 expression is significantly elevated in most human cancers when compared to matched normal tissues [10,11,12,13,14] These reports support the possibility that ongoing, low-level L1 activity can introduce structural genomic rearrangements over the life span of an organism. Once integrated into the genome, copies of L1 and L1-driven retroelements provide abundant substrates for non-allelic homologous recombination events, which have been reported to result in deletions, duplications, translocations and other genomic rearrangements [4,17,18,19,20,21] These types of L1-induced alterations of the genome have resulted in a variety of diseases, including multiple cancers [reviewed in [22]]
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