Abstract 1720 LINE-1 retrotransposons: interactomes, structures, and biomarker assays

I will showcase some of our latest research on LINE-1 (L1) retrotransposons. L1 is the only active, autonomous (protein coding) retrotransposon in humans; non-autonomous SINEs, such as Alu, hijack L1 for their own mobilization. L1 proliferates in genomes through a 'copy-and-paste' mechanism that involves a viral-like ribonucleoprotein intermediate, imbued with immunogenic pathogen associated molecular patterns. L1 proteins (ORF1p, ORF2p) preferentially assemble with the L1 RNA that encodes them (a property termed cis preference), implying a mechanism of assembly that restricts trans complementation. These assemblies are poorly understood and heterogeneous in composition, incorporating many other RNAs and host proteins that form abundant cytoplasmic foci (RNA granules). ORF2p is the 'business end' of L1, possessing the requisite endonuclease and reverse transcriptase activities. Consistent with its mutagenic potential and parasitic properties, L1 is normally silenced in most somatic cells. However, dysregulation of L1 expression is associated with several human diseases - e.g., cancer, autoimmunity, neurodegeneration - and, generally, with aging. L1 therefore represents a promising biomarker opportunity and therapeutic target. I will present (i) some of our latest insights about L1 macromolecular assemblies, (ii) the first experimentally determined structures of the L1 ORF2p reverse transcriptase domain and full length protein, and (iii) ultra-sensitive targeted methods of L1 ORF protein detection and applications as biomarkers.