L1 retrotransposons in human cancers

Abstract

Retrotransposons like L1 are silenced in somatic cells by a variety of mechanisms acting at different levels. Protective mechanisms include DNA methylation and packaging into inactive chromatin to suppress transcription and prevent recombination, potentially supported by cytidine deaminase editing of RNA. Furthermore, DNA strand breaks arising during attempted retrotranspositions ought to activate cellular checkpoints, and L1 activation outside immunoprivileged sites may elicit immune responses. A number of observations indicate that L1 sequences nevertheless become reactivated in human cancer. Prominently, methylation of L1 sequences is diminished in many cancer types and full-length L1 RNAs become detectable, although strong expression is restricted to germ cell cancers. L1 elements have been found to be enriched at sites of illegitimate recombination in many cancers. In theory, lack of L1 repression in cancer might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome disorganization, expression changes, and chromosomal instability. There is however little evidence that such effects occur at a gross scale in human cancers. Rather, as a rule, L1 repression is only partly alleviated. Unfortunately, many techniques commonly used to investigate genetic and epigenetic alterations in cancer cells are not well suited to detect subtle effects elicited by partial reactivation of retroelements like L1 which are present as abundant, but heterogeneous copies. Therefore, effects of L1 sequences exerted on the local chromatin structure, on the transcriptional regulation of individual genes, and on chromosome fragility need to be more closely investigated in normal and cancer cells.

Figure 1

Potential effects of L1 sequences on transcriptional regulation. (a) schematic view of a human gene. One L1 element is located upstream of the gene and one within. Panels (b)–(g) show various disturbances that could be caused by partial or complete reactivation of L1 elements: (b) deregulation by upstream L1 promoter; (c) transcriptional interference by the promoter of an L1 in inverse direction to the gene; (d) generation of an alternative 5′-truncated transcript by an internal L1 promoter in sense direction; (e) generation of an alternative 5′-truncated transcript by the antisense promoter of an internal L1 element in inverse direction to the gene; (f) transcriptional interference by the antisense promoter of an internal L1 element oriented in sense direction; (g) generation of a truncated transcript by use of the poly-adenylation site of an internal L1 element. Note that most effects do not require intact retrotransposons.

Figure 2

Postulated boundary effect of intergenic L1 clusters. Being strongly methylated and tightly packed into chromatin, clustered L1 sequences might act as boundaries between genes, restricting the interaction of an enhancer (ENH) to one gene (a). In cancer cells, L1 hypomethylation could destroy this function and cause deregulation by allowing enhancer interaction with a neighboring gene (b).