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: Jason Brocato, Lei Fang, Yana Chervona, Danqi Chen, Kathrin Kiok, Hong Sun, Hsiang-Chi Tseng, Dazhong Xu, Magdy Shamy, Chunyuan Jin, Max Costa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 46 Pg. 31751-31764 (Nov 14 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25266719 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Histones
• Nuclear Proteins
• RNA, Messenger
• SLBP protein, human
• mRNA Cleavage and Polyadenylation Factors
• Arsenic

Topics

• Arsenic (chemistry)
• Cell Line, Tumor
• Chromosomes (ultrastructure)
• DNA Damage
• Epigenesis, Genetic (drug effects)
• Gene Expression Regulation
• HEK293 Cells
• Histones (chemistry)
• Humans
• Leukocytes, Mononuclear (drug effects)
• Mitosis
• Nuclear Proteins (metabolism)
• Polyadenylation
• Protein Binding
• RNA, Messenger (metabolism)
• S Phase (drug effects)
• mRNA Cleavage and Polyadenylation Factors (metabolism)