Abstract
Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposons in mammalian genomes that remain silent under most conditions. Cellular stress signals activate L1, but the molecular mechanisms controlling L1 activation remain unclear. Evidence is presented here that benzo(a)pyrene (BaP), an environmental hydrocarbon metabolized by mammalian cytochrome P450s to reactive carcinogenic intermediates, increases L1 retrotransposition in HeLa cells. Increased retrotransposition is mediated by up-regulation of L1 RNA levels, increased L1 cDNA synthesis, and stable genomic integration. Activation of L1 is dependent on the ability of BaP to cause DNA damage because it is absent in HeLa cells challenged with nongenotoxic hydrocarbon carcinogens. Thus, the mutations and genomic instability observed in human populations exposed to genotoxic environmental hydrocarbons may involve epigenetic activation of mobile elements dispersed throughout the human genome.
Highlights
Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposon sequences that occupy f17% of the human genome [1, 2]
A functional human L1 element is f6 kb long and consists of a 5V-untranslated region (UTR) with an internal promoter, two open reading frames (ORF1 and ORF2), and a 3VUTR terminating in polyadenylic acid tail [6]
HeLa stable transfectants harboring human L1RP under control of a heterologous cytomegalovirus promoter were treated with benzo(a) pyrene (BaP) (3 Amol/L), and total RNA was analyzed by reverse transcription-PCR (RT-PCR)
Summary
Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposon sequences that occupy f17% of the human genome [1, 2]. A functional human L1 element is f6 kb long and consists of a 5V-untranslated region (UTR) with an internal promoter, two open reading frames (ORF1 and ORF2), and a 3VUTR terminating in polyadenylic acid tail [6]. L1 retrotransposition requires the transcription of L1 RNA, its transport to the cytoplasm, and translation of ORF1 and ORF2. These proteins preferentially associate with their encoding transcript to form a ribonucleoprotein particle [11]. After transport to the nucleus, L1-encoded endonuclease cleaves genomic DNA at degenerate consensus target sequence, TTTT/A, and variants of
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