LINE-1 retrotransposition in human neuroblastoma cells is affected by oxidative stress

Abstract

Long interspersed element-1s (LINE-1 or L1s) are abundant retrotransposons that occur in mammalian genomes and that can cause insertional mutagenesis and genomic instability. L1 activity is generally repressed in most cells and tissues but has been found in some embryonic cells and, in particular, in neural progenitors. Moreover, L1 retrotransposition can be induced by several DNA-damaging agents. We have carried out experiments to verify whether L1 retrotransposition is affected by oxidative DNA damage, which plays a role in a range of human diseases, including cancer and inflammatory and neurodegenerative disease. To this purpose, BE(2)C neuroblastoma cells, which are thought to represent embryonic precursors of sympathetic neurons, have been treated with hydrogen peroxide and subjected to an in vitro retrotransposition assay involving an episomal L1(RP) element tagged with enhanced green fluorescent protein. Our results indicate that hydrogen peroxide treatment induces an increase in the retrotransposition of transiently transfected L1(RP) and an increase in the expression of endogenous L1 transcripts. An increase of γ-H2AX foci and changes in the mRNA levels of MRE11, RAD50, NBN and ERCC1 (all involved in DNA repair) have also been found. Thus, oxidative stress can cause L1 dysregulation.

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

“…increased mobility of yeast Ty1 and mammalian L1 elements in response to oxidative stress and that activation of Ty1 elements by the DNA-damaging agent MMS requires mitochondrial function and ROS production (Stoycheva et al 2010;Giorgi et al 2011). Regulation of retrotransposon expression and mobility by numerous stresses could have consequences for cell function and survival in stressful conditions (Capy et al 2000;Slotkin and Martienssen 2007).…”

“…Some retrotransposons, such as the mammalian L1 element and yeast Ty1 element, are frequently present at sites of chromosome rearrangements and can produce retrotransposed copies of gene transcripts (Derr et al 1991;Esnault et al 2000;Dunham et al 2002;Gilbert et al 2002;Umezu et al 2002;Abeysinghe et al 2003;Maxwell and Curcio 2007;Robberecht et al 2013). Furthermore, mammalian L1 elements and yeast Ty1 elements are both activated by increased reactive oxygen species (ROS) and DNA damage (Rockwood et al 2004;Beauregard et al 2008;Stoycheva et al 2010;Giorgi et al 2011), which are stresses associated with aging (Burhans and Weinberger 2012;Kirkwood and Kowald 2012). However, the potential role of retrotransposons and the genome instability they cause in aging has not yet been well investigated.…”

“…Copy-number control results in reduced Ty1 mobility when many copies of Ty1 are present in the genome, but high Ty1 mobility when only one or a few Ty1 elements are present in the genome. Similarities in regulation by cellular stresses and influences on genome instability between Ty1 and mammalian retrotransposons make Ty1 a good model element for investigating the contribution of retrotransposons to a complex phenotype, such as aging (Beauregard et al 2008;Stoycheva et al 2010;Giorgi et al 2011).…”

LINE-1 in cancer: multifaceted functions and potential clinical implications

“…31,84 Oxidative stress can promote L1 hypomethylation and L1 expression in cancer cell lines, along with disrupted expression of genes involved in DNA repair. 81,82 Additionally, some precancerous conditions, such as chronic inflammation, can stimulate oxidative stress. 85,86 Therefore, oxidative stress-induced L1 activation might represent one of the mechanisms linking chronic inflammation and tumorigenesis, which deserves further investigation.…”

Consequences of ongoing retrotransposition in mammalian genomes

“…[51][52][53][54] Engineered L1 elements can retrotranspose when introduced into human ES cells, human and rat neural progenitor cells, human oocytes, primary human fibroblasts, a variety of cancer cell lines, and retrotranspose at higher levels in response to oxidative stress and ionizing radiation. [29][30][31]36,[55][56][57][58][59] The extent of ongoing retrotransposition in mammals…”