Much of the human genome is repetitive sequence derived from transposable elements. These include copy-and-paste retrotransposons and cut-and-paste DNA transposons. Only retrotransposons are active as undomesticated mobile DNAs in humans.
Ongoing retrotransposition in humans is attributed to long interspersed element-1 (LINE-1; also known as L1). Its activity creates genomic structural variants in human populations and alterations in cancer genomes. Endogenous retroviruses persist as promoter and protein-coding sequences.
LINE-1 encodes open reading frame 1p (ORF1p) and ORF2p proteins. ORF1p is an RNA binding protein widely expressed in human malignancies. ORF2p encodes endonuclease and reverse transcriptase activities essential for retrotransposition.
LINE-1 activity generates new copies of itself, and also other sequences, including Alu and short interspersed element (SINE)–variable number tandem repeat (VNTR)–Alu (SVA) retrotransposons, pseudogene copies of messenger transcripts and U6 ribosomal RNAs (rRNAs).
In cancer, source LINE-1 elements escape genomic DNA methylation and transcriptional repression to contribute new LINE-1 insertions. Different source elements may be active over different phases of the evolution of a cancer.
Somatically acquired LINE-1 insertions can cause driver mutations, particularly in gastrointestinal tract tumours, which support high levels of retrotransposition. Distinguishing contributing mutations from inert passenger mutations is an important challenge for the field.
Transposable elements give rise to interspersed repeats, sequences that comprise most of our genomes. These mobile DNAs have been historically underappreciated — both because they have been presumed to be unimportant, and because their high copy number and variability pose unique technical challenges. Neither impediment now seems steadfast. Interest in the human mobilome has never been greater, and methods enabling its study are maturing at a fast pace. This Review describes the activity of transposable elements in human cancers, particularly long interspersed element-1 (LINE-1). LINE-1 sequences are self-propagating, protein-coding retrotransposons, and their activity results in somatically acquired insertions in cancer genomes. Altered expression of transposable elements and animation of genomic LINE-1 sequences appear to be hallmarks of cancer, and can be responsible for driving mutations in tumorigenesis.
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Johns Hopkins University School of Medicine has licensed long interspersed element-1 (LINE-1) open reading frame 1p (ORF1p) monoclonal antibodies developed in the Burns laboratory for commercial production (K.H.B.).
A mechanism used by transposable elements to copy RNA intermediates to genomic DNA.
- Centromeric satellites
Arrays of tandem, simple repeats at the regions of chromosomes that attach to the mitotic spindle.
- Human reference genome assembly
A version of the human genome, for example, the human Dec. 2013 (GRCh38/hg38) assembly. Structural variants caused by mobile element insertions are not consistently incorporated.
- Source element
Full-length genomic long interspersed element-1 (LINE-1) sequence capable of retrotransposition.
- PIWI-interacting RNAs
(piRNAs). Small RNAs (26–31 nucleotides) that bind to PIWI family proteins and have key roles in silencing retroelements.
- Short read alignments
Alignments of short reads from massively parallel sequencing (MPS) studies to a reference sequence; for example, to the human reference genome assembly.
- Target primed reverse transcription
(TPRT). The molecular process executed by long interspersed element-1 (LINE-1) open reading frame 2p (ORF2p), using a strand of target site DNA to prime reverse transcription of an RNA.
The tendency of long interspersed element-1 (LINE-1)-encoded open reading frame 2p (ORF2p) to associate with and reverse transcribe the RNA strand that encoded the protein. This opposes other RNA species that co-opt ORF2p by association in trans.
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