L1 Retrotransposons in Human Cancers

[摘要] Retrotransposons like L1 are silenced in somatic cells by avariety of mechanisms acting at different levels. Protectivemechanisms include DNA methylation and packaging into inactivechromatin to suppress transcription and prevent recombination,potentially supported by cytidine deaminase editing of RNA.Furthermore, DNA strand breaks arising during attemptedretrotranspositions ought to activate cellular checkpoints, and L1activation outside immunoprivileged sites may elicit immuneresponses. A number of observations indicate that L1 sequencesnevertheless become reactivated in human cancer. Prominently,methylation of L1 sequences is diminished in many cancer types andfull-length L1 RNAs become detectable, although strong expressionis restricted to germ cell cancers. L1 elements have been found tobe enriched at sites of illegitimate recombination in manycancers. In theory, lack of L1 repression in cancer might causetranscriptional deregulation, insertional mutations, DNA breaks,and an increased frequency of recombinations, contributing togenome disorganization, expression changes, and chromosomalinstability. There is however little evidence that such effectsoccur at a gross scale in human cancers. Rather, as a rule, L1repression is only partly alleviated. Unfortunately, manytechniques commonly used to investigate genetic and epigeneticalterations in cancer cells are not well suited to detect subtleeffects elicited by partial reactivation of retroelements like L1which are present as abundant, but heterogeneous copies.Therefore, effects of L1 sequences exerted on the local chromatinstructure, on the transcriptional regulation of individual genes,and on chromosome fragility need to be more closely investigatedin normal and cancer cells.

[学科分类] 基础医学