Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci

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,...

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Main Authors:	Kines, Kristine J., Sokolowski, Mark, deHaro, Dawn L., Christian, Claiborne M., Belancio, Victoria P.
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176336/

id	pubmed-4176336
recordtype	oai_dc
spelling	pubmed-41763362014-12-01 Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci Kines, Kristine J. Sokolowski, Mark deHaro, Dawn L. Christian, Claiborne M. Belancio, Victoria P. Genome Integrity, Repair and Replication 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. Oxford University Press 2014-09-15 2014-08-20 /pmc/articles/PMC4176336/ /pubmed/25143528 http://dx.doi.org/10.1093/nar/gku687 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kines, Kristine J. Sokolowski, Mark deHaro, Dawn L. Christian, Claiborne M. Belancio, Victoria P.
spellingShingle	Kines, Kristine J. Sokolowski, Mark deHaro, Dawn L. Christian, Claiborne M. Belancio, Victoria P. Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
author_facet	Kines, Kristine J. Sokolowski, Mark deHaro, Dawn L. Christian, Claiborne M. Belancio, Victoria P.
author_sort	Kines, Kristine J.
title	Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
title_short	Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
title_full	Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
title_fullStr	Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
title_full_unstemmed	Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci
title_sort	potential for genomic instability associated with retrotranspositionally-incompetent l1 loci
description	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.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176336/
_version_	1613137732128735232

Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci

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