title: Arsenic induces polyadenylation of canonical histone mRNA by down-regulating stem-loop-binding protein gene expression.
abstract: The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3'-end. Instead, the histone mRNAs display a stem-loop structure at their 3'-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. Here we report that exposure to arsenic, a carcinogenic metal, decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increased polyadenylation of canonical histone H3.1 mRNA possibly through down-regulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic was not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels. Excess expression of canonical histones have been shown to increase sensitivity to DNA damage as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic exposure may contribute to arsenic-induced carcinogenesis.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Jason
authors.initials: J
authors.lastname: Brocato
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Yana
authors.initials: Y
authors.lastname: Chervona
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kiok
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Hsiang-Chi
authors.initials: HC
authors.lastname: Tseng
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Dazhong
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Environmental Sciences, Faculty of Meteorology, Environment, and Arid Land Agriculture, King Abdulaziz University, Jeddah 21432, Saudi Arabia.
authors.forename: Magdy
authors.initials: M
authors.lastname: Shamy
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and. Electronic address: Chunyuan.Jin@nyumc.org.
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016 and.
authors.forename: Max
authors.initials: M
authors.lastname: Costa
mesh_terms: D001151:Arsenic / Q000737:chemistry*; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000648:ultrastructure; D004249:DNA Damage; D044127:Epigenesis, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism*; D026723:Polyadenylation; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; C092663:SLBP protein, human; D039221:mRNA Cleavage and Polyadenylation Factors; D001151:Arsenic
keywords: Arsenic; Canonical Histone mRNA; Cell Cycle; Epigenetics; Histone; Metal; Polyadenylation; SLBP