Retrotransposition‐Competent Human LINE‐1 Induces Apoptosis in Cancer Cells With Intact p53

Abstract

Retrotransposition of human LINE-1 (L1) element, a major representative non-LTR retrotransposon in the human genome, is known to be a source of insertional mutagenesis. However, nothing is known about effects of L1 retrotransposition on cell growth and differentiation. To investigate the potential for such biological effects and the impact that human L1 retrotransposition has upon cancer cell growth, we examined a panel of human L1 transformed cell lines following a complete retrotransposition process. The results demonstrated that transposition of L1 leads to the activation of the p53-mediated apoptotic pathway in human cancer cells that possess a wild-type p53. In addition, we found that inactivation of p53 in cells, where L1 was undergoing retrotransposition, inhibited the induction of apoptosis. This suggests an association between active retrotransposition and a competent p53 response in which induction of apoptosis is a major outcome. These data are consistent with a model in which human retrotransposition is sensed by the cell as a "genetic damaging event" and that massive retrotransposition triggers signaling pathways resulting in apoptosis.

L1 mobile element expression causes multiple types of toxicity

“…This work goes on to suggest that this diminished retrotransposition is the result of Bax-induced apoptosis (Haoudi et al, 2004). Indeed, it has also been shown that L1 expression can induce apoptosis in MCF7 cells, a cell line with wild type p53 (Gasior et al, 2006a;Shiloh 2003;Haoudi et al, 2004).…”

“…This work goes on to suggest that this diminished retrotransposition is the result of Bax-induced apoptosis (Haoudi et al, 2004). Indeed, it has also been shown that L1 expression can induce apoptosis in MCF7 cells, a cell line with wild type p53 (Gasior et al, 2006a;Shiloh 2003;Haoudi et al, 2004). As expected, we observe very little retrotransposition when a tagged L1 retrotransposition cassette is transfected into MCF7 cells, despite relatively high transfection and colony-forming efficiencies as measured by parallel transfection of a hygromycin resistance cassette ( Figure 1B).…”

“…Their repair has a high rate of error leading to the loss of genetic information as well as chromosomal rearrangements (Longhese et al, 2006). DSBs can lead to apoptosis, and it has been hypothesized that this is how L1 expression leads to apoptosis (Haoudi et al, 2004). However, genomic damage can also be associated with other types of cellular response, such as cellular senescence, a cellular endpoint of permanent cell cycle arrest (Gire et al, 2006;Houtgraaf et al, 2006).…”

“…After showing that this induction preceded p53 mutations during the progression of human bladder tumors, Bartek et al hypothesized that induction of the ATM pathway acted as a selective pressure promoting mutations like those commonly seen in p53 in order to avoid its pro-apoptotic signals (Bartkova et al, 2005). Because mutations of p53 are typically associated with human cancer progression, the induction of this DNA damage response associated with L1 expression may play a role in human cancer progression (Gasior et al, 2006a;Haoudi et al, 2004). While evidence of the deleterious nature of L1 expression is widespread, the exact domains of L1 contributing to the various cellular responses, as well as the full range of cellular responses to L1 have been only poorly characterized to date.…”

Repeated Recruitment of LTR Retrotransposons as Promoters by the Anti-apoptotic Locus NAIP During Mammalian Evolution

“…Infection by retroviruses can lead to induction of apoptosis [66,67], and HIV Nef activates caspases [66], the targets of IAP proteins. Waves of intracellular retrotransposition can also be associated with increased apoptosis [68]. Therefore, retroviral/retroelement insertions in germ line cells which, by chance, induce expression of anti-apoptotic genes, could abort an initial or transitory stress-induced apoptotic response, increasing the probability that cells harboring such insertions would survive and contribute to subsequent generations, assuming they have not suffered damage.…”