Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night

Abstract

Expression of long interspersed element-1 (L1) is upregulated in many human malignancies. L1 can introduce genomic instability via insertional mutagenesis and DNA double-strand breaks, both of which may promote cancer. Light exposure at night, a recently recognized carcinogen, is associated with an increased risk of cancer in shift workers. We report that melatonin receptor 1 inhibits mobilization of L1 in cultured cells through downregulation of L1 mRNA and ORF1 protein. The addition of melatonin receptor antagonists abolishes the MT1 effect on retrotransposition in a dose-dependent manner. Furthermore, melatonin-rich, but not melatonin-poor, human blood collected at different times during the circadian cycle suppresses endogenous L1 mRNA during in situ perfusion of tissue-isolated xenografts of human cancer. Supplementation of human blood with exogenous melatonin or melatonin receptor antagonist during the in situ perfusion establishes a receptor-mediated action of melatonin on L1 expression. Combined tissue culture and in vivo data support that environmental light exposure of the host regulates expression of L1 elements in tumors. Our data imply that light-induced suppression of melatonin production in shift workers may increase L1-induced genomic instability in their genomes and suggest a possible connection between L1 activity and increased incidence of cancer associated with circadian disruption.

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

“…1 Our recent findings illustrate several novel features of L1 biology directly relevant to human health. Specifically, we highlight a new dimension to the complex regulation of both L1 expression and damage through the unforeseen connection between L1, the host's circadian system, and environmental light exposure at night in vivo.…”

“…1 Analysis of endogenous human L1 expression in PC3-derived xenografts perfused with human blood collected at noon or midnight as well as at night after exposure to bright light demonstrated that night-time blood suppresses L1 expression. The addition of exogenous melatonin to melatonin-poor blood during perfusion suppressed L1 expression; while the addition of non-selective antagonist of melatonin receptors during perfusion with melatonin-rich blood restored detection of L1 mRNA in tumor samples.…”

Development of a monoclonal antibody specific to the endonuclease domain of the human LINE-1 ORF2 protein

“…L1 expression and retrotransposition are suppressed by many diverse cellular pathways in order to minimize the genomic damage inflicted by L1 activity [20,[43][44][45][46][47][48][49][50]. L1 encodes an ORF2 protein with several identified functions essential for the retrotransposition process.…”

Melatonin: an inhibitor of breast cancer

“…The Belancio laboratory has recently reported that melatonin, via the MT 1 receptor mediated action, suppresses expression of the endogenous retrotransposon L1 in a tissue-isolated model of human cancer (Deharo et al 2014). This finding supports that LEN-induced suppression of nocturnal melatonin synthesis activates L1 expression.…”