Restricting retrotransposons: a review

Abstract

Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic “parasites”, focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation. Some factors act in the nucleus and involve DNA repair enzymes or epigenetic processes of DNA methylation and histone modification. RISC and piRNA pathway proteins protect the germline. Retrotransposon control is relaxed in some cell types, such as neurons in the brain, stem cells, and in certain types of disease and cancer, with implications for human health and disease. This review also considers potential pitfalls in interpreting retrotransposon-related data, as well as issues to consider for future research.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

“…Hence, at least some mouse L1 families may be highly predisposed to generate full-length offspring L1 insertions in the germline (Hardies et al 2000;Richardson et al 2017) as well as in cancer cells. In contrast, L1 insertions detected in human tumors are predominantly 5 ′ truncated (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Shukla et al 2013;Helman et al 2014;Tubio et al 2014;Doucet-O'Hare et al 2015, 2016Ewing et al 2015;Paterson et al 2015;Rodic et al 2015;Scott et al 2016) and involve structural rearrangements at a higher frequency than for L1 insertions arising in the human germline (Gardner et al 2017). These differences are apparent even among hominids.…”

“…For example, the rate of germline L1 5 ′ inversion appears to be lower in chimpanzee than in human (Gardner et al 2017). Whether these observations reflect species-specific differences in the enzymatic properties of L1s or the cellular environment in which retrotransposition events occur, including host factors such as the APOBEC (also known as AID) proteins that are more diverse in humans than in rodents (Goodier 2016), remains to be determined.…”

“…In 1992, Miki et al identified an exonic L1 insertion into the APC gene that very likely led to tumor initiation in a case of colorectal cancer, providing the first direct evidence for L1 involvement in oncogenesis (Miki et al 1992). Since then, spurred by the advent of high-throughput sequencing approaches for identifying endogenous somatic L1 insertions, L1 mobilization events have been uncovered in a plethora of tumor types, including lung, ovarian, breast, colorectal, prostate, liver, pancreatic, gastric, endometrial, and esophageal cancers (Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Shukla et al 2013;Helman et al 2014;Tubio et al 2014;Doucet-O'Hare et al 2015, 2016Ewing et al 2015;Paterson et al 2015;Rodic et al 2015;Scott et al 2016). Although these studies have elucidated driver L1 mutations exonic to APC and PTEN, most of the cataloged tumor-specific L1 insertions represent likely passenger events (Helman et al 2014;Scott et al 2016).…”

On the Concept Of Retrotransposons: Controlling Genome and Making Stress Memories

“…To ensure as much as possible the integrity and fidelity of genetic information flow, the cell has evolved several control mechanisms to regulate retrotransposon activity [38][39][40] . The epigenetic control of genome, a process likely originated in response to TEs activity, through several mechanisms such as cellular environment, DNA methylation, histone methylation and RNA interference pathways (siRNA, miRNA, piRNA, rasiRNA, endo-siRNA) previously reviewed [38,[41][42][43][44][45][46] , is responsible for retrotransposon repression. Nevertheless, nowadays retrotransposons are active playing major roles inthe plasticity and regulation of the host genome.…”

“…Third, retrotransposons are capable of altering epigenetically host gene expression [1,106] . Their regulation, through different epigenetic systems [38,[41][42][43][44][45][46] , has established a close relationship between the expression of a given retrotransposon and the respective of an adjacent gene. Interestingly, host mechanisms are often involved in altered gene expression, as the formation of heterochromatin by retrotransposons-targeting repressors can subsequently spread to adjacent genes [38,83,91] .…”