title: 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.
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA Tulane Center for Aging, New Orleans, LA 70112, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: deHaro
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA Tulane Center for Aging, New Orleans, LA 70112, USA.
authors.forename: Kristine J
authors.initials: KJ
authors.lastname: Kines
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA Tulane Center for Aging, New Orleans, LA 70112, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sokolowski
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Streva
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
authors.affiliation: Department of Neurology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Hanifin
authors.affiliation: Department of Neurology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Brainard
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.affiliation: Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA Tulane Center for Aging, New Orleans, LA 70112, USA vperepe@tulane.edu.
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Belancio
mesh_terms: D020087:Alu Elements; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003624:Darkness; D006801:Humans; D008027:Light; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008550:Melatonin / Q000097:blood / Q000502:physiology*; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012306:Risk; D054875:Ubiquitination / Q000235:genetics
chemical_list: C531245:ORF1 protein, human; D011506:Proteins; D012333:RNA, Messenger; D044122:Receptor, Melatonin, MT1; D008550:Melatonin