Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells

Lu, Kim P.; Hallberg, Lance; Tomlinson, Jeff; Ramos, Kenneth S.

doi:10.1016/s0027-5107(00)00095-6

Cited by 36 publications

(28 citation statements)

References 38 publications

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“…Expression of L1 retrotransposon sequences is up-regulated in mouse somatic cells challenged acutely with BaP or its oxidative metabolites as determined by Northern blot analysis, differential display, and realtime PCR (27)(28)(29). To determine if BaP treatment activates human L1 expression and increases L1 retrotransposition, a plasmid-based strategy was employed using cultured HeLa cells.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we reported that expression of L1 retrotransposon sequences is dramatically up-regulated in mouse vascular smooth muscle cells challenged with BaP or its oxidative metabolites as determined by Northern blot analysis, differential display, and DNA microarrays (27)(28)(29). Moreover, a novel retrotransposon of mouse L1Md-A2 lineage was found in vascular smooth muscle cells that contain two antioxidant responsive elements in its 5V -UTR region and participate in transactivation (29).…”

Section: Discussionmentioning

confidence: 96%

“…We have shown previously that benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon carcinogen, activates L1 expression in various cell types (27)(28)(29). L1 activation by BaP requires cytochrome P450-catalyed oxidation of the parent hydrocarbon to oxygenated intermediates that adduct DNA (28).…”

Section: Introductionmentioning

confidence: 99%

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Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Stribinskis

Ramos

2006

Cancer Research

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Stribinskis

Ramos

2006

Cancer Research

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“…Factors known to activate retrotransposons include radiation (16,17), chemical carcinogens (18,19), and stress-related factors (20,21). Retrotransposon activation may play a role in evolution of the genome (22), double strand break DNA repair (23), exon shuffling (24,25), and diseases caused by insertional mutation in both human (26 -29) and mice (30 -34).…”

mentioning

confidence: 99%

“…Previous studies in this laboratory (18) have shown that benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon carcinogen and atherogen, activates L1Md expression in mouse vascular smooth muscle cells. L1Md activation is also elicited by oxidative metabolites of the parent hydrocarbon, suggesting that modulation of redox homeostasis mediates epigenetic disruption of gene expression and possibly DNA damage (19).…”

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confidence: 99%

Redox Regulation of a Novel L1Md-A2 Retrotransposon in Vascular Smooth Muscle Cells

Ramos

2003

Journal of Biological Chemistry

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Activation and reintegration of retrotransposons into the genome is linked to several diseases in human and rodents, but mechanisms of gene activation remain largely unknown. Here we identify a novel gene of L1Md-A2 lineage in vascular smooth muscle cells and show that environmental hydrocarbons enhance gene expression and activate monomer-driven transcription via a redox-sensitive mechanism. Site-directed mutagenesis and progressive deletion analyses identified two antioxidant/electrophile response-like elements (5-GTGACTCGAGC-3) within the A2/3 and A3 region. These elements mediated activation, with the A3 monomer playing an essential role in transactivation. This signaling pathway may contribute to gene instability during the course of atherogenesis.

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Long INterspersed element‐1 mobility as a sensor of environmental stresses

Giorgi

2020

Environ and Mol Mutagen

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Long INterspersed element (LINE-1, L1) retrotransposons are the most abundant transposable elements in the human genome, constituting approximately 17%. They move by a "copy-paste" mechanism, involving reverse transcription of an RNA intermediate and insertion of its cDNA copy at a new site in the genome. L1 retrotransposition (L1-RTP) can cause insertional mutations, alter gene expression, transduce exons, and induce epigenetic dysregulation. L1-RTP is generally repressed; however, a number of observations collected over about 15 years revealed that it can occur in response to environmental stresses. Moreover, emerging evidence indicates that L1-RTP can play a role in the onset of several neurological and oncological diseases in humans. In recent years, great attention has been paid to the exposome paradigm, which proposes that health effects of an environmental factor should be evaluated considering both cumulative environmental exposures and the endogenous processes resulting from the biological response. L1-RTP could be an endogenous process considered for this application. Here, we summarize the current understanding of environmental factors that can affect the retrotransposition of human L1 elements. Evidence indicates that L1-RTP alteration is triggered by numerous and various environmental stressors, such as chemical agents (heavy metals, carcinogens, oxidants, and drugs), physical agents (ionizing and non-ionizing radiations), and experiential factors (voluntary exercise, social isolation, maternal care, and environmental light/dark cycles). These data come from in vitro studies on cell lines and in vivo studies on transgenic animals: future investigations should be focused on physiologically relevant models to gain a better understanding of this topic.

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Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells

Cited by 36 publications

References 38 publications

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Redox Regulation of a Novel L1Md-A2 Retrotransposon in Vascular Smooth Muscle Cells

Long INterspersed element‐1 mobility as a sensor of environmental stresses

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