LINE-1 ORF1 protein enhances Alu SINE retrotransposition

Wallace, Nicholas A.; Wagstaff, Bradley J.; Deininger, Prescott L.; Roy-Engel, Astrid M.

doi:10.1016/j.gene.2008.04.007

Cited by 86 publications

(105 citation statements)

References 52 publications

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“…This represents the first identification of a likely source element for a disease-causing Alu element and illustrates how our increasing understanding of the factors influencing Alu element activity can help us predict the potential strength of individual Alu elements and potentially predict likely source elements for other Alu insertions causing disease. In a number of our studies, the level of expression of ORF2p driving the tagged Alu insertion (Wallace et al 2008) appeared to have a significant influence. Most studies using this Alu retrotransposition assay make use of either overexpression of an L1 or simply of ORF2 from L1.…”

Section: (Students Paired T-test) (C)mentioning

confidence: 76%

Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Comeaux¹,

Roy-Engel²,

Hedges³

et al. 2009

Genome Res.

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The human genome contains nearly 1.1 million Alu elements comprising roughly 11% of its total DNA content. Alu elements use a copy and paste retrotransposition mechanism that can result in de novo disease insertion alleles. There are nearly 900,000 old Alu elements from subfamilies S and J that appear to be almost completely inactive, and about 200,000 from subfamily Y or younger, which include a few thousand copies of the Ya5 subfamily which makes up the majority of current activity. Given the much higher copy number of the older Alu subfamilies, it is not known why all of the active Alu elements belong to the younger subfamilies. We present a systematic analysis evaluating the observed sequence variation in the different sections of an Alu element on retrotransposition. The length of the longest number of uninterrupted adenines in the A-tail, the degree of A-tail heterogeneity, the length of the 3′ unique end after the A-tail and before the RNA polymerase III terminator, and random mutations found in the right monomer all modulate the retrotransposition efficiency. These changes occur over different evolutionary time frames. The combined impact of sequence changes in all of these regions explains why young Alus are currently causing disease through retrotransposition, and the old Alus have lost their ability to retrotranspose. We present a predictive model to evaluate the retrotransposition capability of individual Alu elements and successfully applied it to identify the first putative source element for a disease-causing Alu insertion in a patient with cystic fibrosis.

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Section: (Students Paired T-test) (C)mentioning

confidence: 76%

Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Comeaux¹,

Roy-Engel²,

Hedges³

et al. 2009

Genome Res.

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“…Functional full-length L1 transcripts contain two open reading frames (ORFs) encoding ORF1 and ORF2 proteins (ORF1p and ORF2p, respectively) ( Figure 1A). These L1 proteins exhibit cis-preference for their encoding L1 mRNA [5][6][7] and are utilized in trans by the Alu and SVA elements [2,3,8]. L1, Alu, and SVA form ribonucleoprotein (RNP) particles which reach the nucleus to complete their replication cycles by integrating in the host genome via a process of target-primed reverse transcription [9,10].…”

Section: Introductionmentioning

confidence: 99%

Development of a monoclonal antibody specific to the endonuclease domain of the human LINE-1 ORF2 protein

et al. 2014

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Background: LINE-1 (L1) retrotransposons are common occupants of mammalian genomes representing about a fifth of the genetic content. Ongoing L1 retrotransposition in the germ line and somatic tissues has contributed to structural genomic variations and disease-causing mutations in the human genome. L1 mobilization relies on the function of two, self-encoded proteins, ORF1 and ORF2. The ORF2 protein contains two characterized domains: endonuclease and reverse transcriptase. Results: Using a bacterially purified endonuclease domain of the human L1 ORF2 protein, we have generated a monoclonal antibody specific to the human ORF2 protein. We determined that the epitope recognized by this monoclonal antibody includes amino acid 205, which is required for the function of the L1 ORF2 protein endonuclease. Using an in vitro L1 cleavage assay, we demonstrate that the monoclonal anti-ORF2 protein antibody partially inhibits L1 endonuclease activity without having any effect on the in vitro activity of the human AP endonuclease.

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“…1,7 Retrotransposition of human Alu and SVA elements minimally requires L1 ORF2p, 15,17 but ORF1p increases Alu mobilization and is needed to mobilize some SVA elements. 17,21 L1 elements can also mobilize reporter gene transcripts, which requires both ORF1p and ORF2p, providing support for the role of L1 in generating retrocopies of cellular RNA that do not code for proteins (processed pseudogenes) or that do code for proteins and that are expressed from heterologous promoters at target sites (retrogenes). 22 Mice, but not humans, also harbor mobile LTR retrotransposons/ERVs.…”

Section: Advances In Genomics Andmentioning

confidence: 95%

Consequences of ongoing retrotransposition in mammalian genomes

Maxwell

2014

AGG

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Abstract:Retrotransposons can have significant influences on gene expression and genome stability through their ability to integrate reverse-transcript copies of their sequences at new genomic locations by retrotransposition. These elements have been long known to retrotranspose in mammalian germ cells to give rise to inherited insertion alleles, but more recent work has also shown that retrotransposition can occur in mammalian somatic cells, particularly in brain tissue and tumors. Retrotransposition makes appreciable contributions to spontaneous diseasecausing alleles in humans and a more significant contribution to spontaneous mutations in mice. Genome-wide studies have found high levels of polymorphic retrotransposon insertions in human populations that are consistent with ongoing retrotransposition. Many insertions do not disrupt exons, but insertions into introns or flanking genes can alter gene expression patterns, generate truncated or antisense gene transcripts, alter splicing patterns, or result in premature polyadenylation of gene transcripts. Furthermore, the very high genomic copy numbers of these elements can lead to nonallelic homologous recombination events that produce gene deletions/ duplications and genome rearrangements, and can also lead to evolution of particular insertions or types of elements to have cellular functions through exaptation. Mobility of these elements occurs despite multiple epigenetic mechanisms to restrict their expression. While the potential for retrotransposons to significantly influence mammalian health and cellular functions is clear, substantial research efforts will be needed to fully elucidate the actual contributions of natural levels of mobility of endogenous elements to the health and development of humans and other mammals.

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LINE-1 ORF1 protein enhances Alu SINE retrotransposition

Cited by 86 publications

References 52 publications

Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Diverse cis factors controlling Alu retrotransposition: What causes Alu elements to die?

Development of a monoclonal antibody specific to the endonuclease domain of the human LINE-1 ORF2 protein

Consequences of ongoing retrotransposition in mammalian genomes

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