Where to Draw the LINE-Are Retrotransposable Elements Here to Stay?

Abstract

The frequency of somatic retrotranspositions of Long Interspersed Nuclear Elements 1 (LINE1) over a lifetime in healthy colonic epithelium and colorectal tumors has recently been reported. Indicative of a cell type-specific effect, LINE1 sequences in colonic epithelium showed lower levels of DNA methylation compared to other cell types examined in the study. Consistent with a role for DNA methylation in transposon silencing, the decreases in DNA methylation observed at LINE1 elements in colonic epithelium were accompanied by increases in LINE1 mRNA levels. In human primary colorectal tumors, LINE1 retrotransposition frequency was tenfold higher than in normal colonic tissues, with insertions potentially altering genomic stability and cellular functions. Here, we discuss the discoveries made by Nam and colleagues, emphasizing the intestinal-specific methylation signature regulating the LINE1 lifecycle and how this new information could shape future drug discovery endeavors against colorectal cancer.

Keywords: LINE1; colorectal cancer; epigenetics; methylation; retrotransposons; viral mimicry.

Figure 1

The LINE1 lifecycle. LINE1 retrotransposition is a highly regulated, multi-step process that allows for the mobility and insertion of long interspersed nuclear elements in the genome. Following demethylation, LINE1 elements transcription is driven by a promoter located in their 5′ untranslated region (5′-UTR). Upon modifications stabilizing the LINE1 transcripts, LINE1 open reading frames are translated in the cytoplasm. LINE1 open reading frames encode two distinct proteins: ORF2, which possesses endonuclease and reverse transcriptase activities, and ORF1, which functions as a nucleic acid chaperone responsible for ribonucleoprotein particle (RNP) assembly. Both proteins are critical for the association of LINE1 RNA and the formation of a LINE1-RNP intermediate complex. This complex is imported into the nucleus either passively during cell division or actively through interactions with nucleoporin proteins (e.g., KPNA2). Here, the reverse transcriptase and endonuclease activities of ORF2 synthesize a complementary DNA strand and integrate it into a new genomic location. LINE1-derived double-stranded RNA (dsRNA) generated by inter or intramolecular complementarity, cDNA, and LINE1 RNA:DNA hybrids in the cytoplasm can trigger an antiviral-like innate immune response. Due to truncations, internal rearrangements, and mutations frequently occurring through the lifecycle, most newly integrated LINE1 copies are not competent for further retrotransposition. Created with BioRender.com (accessed on 10 August 2023).