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. 2015 Apr 7;5(3):1-5.
doi: 10.1080/2159256X.2015.1037416. eCollection 2015 May-Jun.

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

Victoria P Belancio  1
Affiliations

LINE-1 activity as molecular basis for genomic instability associated with light exposure at night

Victoria P Belancio. Mob Genet Elements. .

Abstract

The original hypothesis that exposure to light at night increases risk of breast cancer via suppression of nocturnal melatonin production was proposed over 2 decades ago. In 2007, shift work that involves circadian disruption has been recognized by the World Health Organization as a probable human carcinogen. Our discovery of melatonin-dependent regulation of LINE-1 retrotransposon expression and mobilization is the latest addition to the list of cellular genes and processes that are affected by light exposure at night. This finding establishes an unexpected health relevant connection between this endogenous DNA damaging agent and environmental light exposure. It also offers an appealing hypothesis pertaining to the origin of genomic instability in the genomes of individuals with light at night- or age-associated disruption of melatonin signaling.

Keywords: DNA damage; LINE-1; aging; cancer; genomic instability; light exposure at night; melatonin; melatonin receptor; retroelements; shift-work.

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Figures

Figure 1.
Figure 1.
Genomic instability associated with L1 activity. A functional full-length L1 element contains a polymerase II promoter in its 5′ untrunslated region and 2 open reading frames ORF1 (blue) and ORF2 (black), which encode proteins necessary for L1 retrotransposition. Both proteins associate with the L1 mRNA to form ribonucleoprotein (RNP) particles that are considered to be retrotranspositional intermediates. The ORF1p functions as a trimer, which has a nucleic acid chaperon activity. The ORF2p contains an endonuclease (EN) and reverse transcriptase activities (RT) critical for nicking genomic DNA and generating L1 cDNA. Either as a part of the L1 RNP or as a “loose” protein, the ORF2p is responsible for the generation of DNA double strand breaks (DSBs). L1 has a potential to contribute to genomic instability through retrotransposition, non-allelic homeologous recombination between integrated L1 or SINE Alu sequences, and DSBs.
Figure 2.
Figure 2.
Many diverse known and yet unidentified cellular proteins and pathways suppress LINE-1 Alification by preventing L1 expression or integration. Some of the proteins and processes reported to affect L1 expression or integration are shown.
Figure 3.
Figure 3.
Proposed mechanism of melatonin-induced suppression of L1 mobilization. mRNA expression of functional L1 loci results in translation of L1 encoded ORF1 and ORF2 proteins (blue and black circles, respectively). The L1 mRNA and proteins associate to form L1 ribonucleoprotein (RNP) particles that undergo retrotrotransposition resulting in L1-associated genomic instability. Nocturnal melatonin production (purple triangles) activates G-coupled melatonin receptors leading to activation of melatonin receptor signaling network, which includes multiple kinases. Our data suggest that activation of this melatonin receptor signaling cascade results in ORF1p phosphorylation (−p) at one or more putative phosphorylation sites. Our results support that the phosphorylated ORF1p is targeted for ubiquitination (−Ub) and proteosomal degradation accounting for the reduced ORF1p levels and retrotransposition detected in the presence of melatonin receptor 1. This mechanism would be consistent with the mechanism of melatonin receptor-dependent suppression of other cellular proteins, which involves phosphorylation-induced ubiquitination targeting these proteins for proteosomal degradation. Solid arrows identify established events, dashed arrows represent events proposed based on our findings. Exposure to artificial light at night (LAN), which occurs during shift work, suppresses nocturnal melatonin synthesis blocking its downregulation of L1-induced genomic instability. Therefore, our data suggest that exposure to LAN may increase L1-induced genomic instability, which could contribute to the increased risk of cancer associated with shift work.
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