School of Chemistry and Molecular Biosciences, The University of Queensland
LINE-1 is a mobile genetic element that replicates throughout the human genome using a copy and paste mechanism termed retrotransposition. Intact LINE-1 elements are bicistronic, encoding two proteins (ORF1p and ORF2p) which drive the mobilisation of LINE1 and other RNAs. ORF1p is a molecular chaperone, while ORF2p contains both endonuclease and reverse transcriptase domains, and is the functional subunit driving retrotransposition in the human genome. LINE-1 elements are transcriptionally repressed in most somatic tissues, but become transcriptionally active in epithelial cancers. Others and I have previously demonstrated the mobilisation of LINE-1 elements in multiple epithelial cancers (including hepatocellular carcinoma, breast cancer, ovarian cancer, esophageal cancer), demonstrating one obvious mechanism of genomic mutation. When considering the impact of LINE-1 mobilisation, it is important to note that relatively few insertions are identified within individual tumours, especially when compared to the mobilisation rate I have described in single human neurons and glia (Upton et. al., Cell 2015). Interestingly, most tumour specific LINE-1 insertions are heavily truncated, suggesting retrotransposition is commonly interrupted. Considering this, and the description of orphan retrotransposition events, where no discernible LINE-1 sequence is identified, it is likely that LINE-1 endonuclease is much more active in epithelial cancers than indicated by the observed retrotransposition rates. Here I assess the existing evidence for LINE-1 acting as a causative agent for genomic instability and mutagenesis, and describe the development and application of novel DNA sequencing techniques to define the extent and impact of LINE1 endonuclease activity in epithelial cancers.