Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

Abstract

Sequence studies of the human genome demonstrate that almost half of the DNA is derived from mobile elements. Most of the current retrotransposition activity arises from L1 and the L1-dependent, non-autonomous elements, such as Alu, contributing to a significant amount of genetic mutation and genomic instability. We present data demonstrating that nickel chloride, but not cobalt chloride, is able to stimulate L1 retrotransposition about 2.5-fold. Our data suggest that the stimulation occurs at a post-transcriptional level, possibly during the integration process. The effect of nickel on the cell is highly complex, limiting the determination of the exact mechanism of this stimulation. The observed stimulation of L1 retrotransposition is not due to a general increase in L1 transcription or an increase in the number of genomic nicks caused by nickel, but more likely caused by a decrease in DNA repair activities that influence the downstream events of retrotransposition. Our observations demonstrate the influence of environmental toxicants on human retroelement activity. We present an additional mechanism for heavy-metal carcinogenesis, where DNA damage through mobile element activation must be considered when dealing with genomic damage/instability in response to environmental agents.

Jumping genes and epigenetics: Towards new species

“…In addition, diet changes, temperature variations, stress etc. could all affect TE transposition (El-Sawy et al, 2005;Hashida et al, 2006;Ebina and Levin, 2007;Cho et al, 2008). Consequently, activation of TEs could result from the relaxation of epigenetic control induced by environmental changes.…”

The impact of multiple splice sites in human L1 elements

“…The open reading frames were cloned into the expression vector pBudCE4.1 (InVitrogen), under control of the CMV promoter. The 5′ UTR expression vector was constructed by subcloning L1.3 5′ UTR sequence into pGL3-basic vector (Promega) to drive the expression of the Firefly luciferase gene (El Sawy et al, 2005).…”

Vanadium Induces VL30 Retrotransposition at an Unusually High Level: A Possible Carcinogenesis Mechanism

“…28 Both paraquat and VOSO 4 induced DSBs (Figure 6(b)) but only the latter resulted in retrotranspositions (Figure 6(a)), consistent with previous findings showing that DSBs alone were not sufficient to stimulate retrotransposition of LINE-1. 46 Based on these data we concluded that, first, VL30s and Ty1 elements have different retrotransposition properties, as if VL30s were involved in repairing damaged DNA, as Ty1 elements, 38 then one would expect retrotranspositions to be induced following paraquat treatment. However, this was not the case.…”

“…Furthermore, if other LTR-retrotransposons, consisting of ∼4% of interspersed repeats in the mouse genome, 12 were affected by vanadium then the total insertion burden might severely assault the genome integrity and produce accumulative genetic damage contributing to cellular transformation, as previously suggested. 46 We believe that these genome consequences can be prevented with antiviral drugs such as efavirenz, shown to reduce induced retrotranspositions (Figure 4(d)), serving a targeted inhibition of retrotransposition.…”