Stem-loop binding protein and metal carcinogenesis

Abstract

Pre-mRNA processing of the replication-dependent canonical histone mRNAs requires an endonucleolytic cleavage immediately after a conserved stem loop structure which occurs before RNA Pol II encounters any poly(A) signal. Thus, in contrast to all other eukaryotic mRNAs, the canonical histone mRNAs are not polyadenylated in their 3' ends. The binding of stem-loop binding protein (SLBP) to the stem loop structure of the histone mRNAs is required for this process. SLBP is also involved in regulation of histone mRNA nuclear export, degradation, and translation. Depletion of SLBP has been shown to induce polyadenylation of histone mRNAs and alteration of histone protein levels, which are considered to contribute to the observed aberrant cell cycle progress and genomic instability resulting from the loss of SLBP function. Recent studies have demonstrated that some heavy metal carcinogens, including arsenic and nickel, can induce the loss of SLBP and the gain of polyadenylation of canonical histone mRNAs. Polyadenylated canonical histone H3 can result in abnormal transcription, cell cycle arrest, genomic instability, and cell transformation, which links SLBP depletion and subsequent histone mRNA misprocessing to cancer. This review seeks to briefly summarize what is known about regulation of SLBP expression, consequences of SLBP depletion, its roles in cancer-related end points, with particular focus on metal-induced SLBP depletion and the potential of SLBP depletion as a new mechanism for metal-induced carcinogenesis.

Keywords: Carcinogenesis; Heavy metal; Histone; Polyadenylation; Stem-loop binding protein.

Figure 1.. A schematic summarizing the regulation and functions of SLBP in normal cells and in the cells exposed to heavy metals.

SLBP is a key regulator of canonical histone mRNAs. It binds to the stem-loop structure in the 3’ end of canonical histone pre-mRNAs, regulating their 3’ end processing, nuclear export, translation, and stability. SLBP is cell-cycle regulated with peak levels in S phase. SLBP protein is maintained at low levels outside of S phase, by proteasome-mediated degradation. SLBP protein is ubiquitinated and degraded by ubiquitin E3 ligase CRL2^FEM1A/B/C in G1 and by SCF^{Cyclin F} in G2 phase, respectively. Phosphorylation at Thr62 by CDK1/Cyclin A primes SLBP for phosphorylation at Thr61 by CK2 at the end of S phase, initiating subsequent SCF^{Cyclin F}-mediated SLBP degradation in G2. SLBP is critical for the maintenance of histone homeostasis, proper chromatin structure and cellular processes in normal cells. Exposure to heavy metals, such as arsenic and nickel, induces depletion of SLBP by both proteasome-mediated protein degradation and transcriptional silencing by epigenetic mechanisms. Depletion of SLBP causes abnormal 3’ end processing by adding a poly(A) tail to canonical histone mRNAs. Polyadenylated canonical histone H3.1 mRNA is stable, leading to the increase in H3.1 protein level and subsequently an imbalance in H3.1 and H3.3 stoichiometry. This results in displacement of H3.3 at important gene regulatory regions, which causes abnormal transcription, cell cycle arrest, chromosome instability, and cell transformation. Further study is needed to be done in the future for a better understanding of SLBP regulation by environmental exposures and its roles in environmental diseases such as cancer.