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Cell cycle regulation of the stem loop binding protein : a key regulator in histone mRNA metabolism

Authors
Publisher
University of North Carolina at Chapel Hill. Library
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Disciplines
  • Biology

Abstract

Metazoan replication-dependent histone mRNAs are unique among eukaryotic mRNAs since they lack polyadenylated tails, instead ending in a conserved stem-loop. Expression of these histone mRNAs is tightly cell cycle regulated mostly via posttranscriptional mechanisms which are mediated by the 3’ stem-loop. The stem loop binding protein (SLBP), which binds to 3’ end of histone mRNAs, plays a major role in histone mRNA metabolism by participating in multiple steps including histone mRNA processing, translation and stability. SLBP expression is limited to S phase, and cell-cycle regulation of SLBP is one of the major mechanisms that restrict histone mRNA biosynthesis and thus histone production to the S phase. The SLBP level is quite low during G1 and it dramatically increases towards S phase. It has been shown that the low level of SLBP at early G1 is due to the low translation efficiency of SLBP mRNA and the translation of SLBP is activated as cells approach S phase. At the end of S phase, SLBP is rapidly degraded depending on phosphorylations of two threonines in N-terminal SFTTP sequences. In this dissertation, I have further elucidated the molecular details of the mechanisms involved in cell cycle regulation of SLBP expression. I have determined Cyclin A/Cdk1 as the kinase that triggers degradation of SLBP at the end of S phase by phosphorylating SLBP Thr61. Cyclin A/Cdk1 activity is cell cycle regulated similar to SLBP Thr61 phosphorylation and is the major activity in late S-phase cells that phosphorylates Thr61. We propose that as Cyclin A/Cdk1 activity reaches to certain level near the end of S-phase, and it triggers SLBP degradation as one of the mechanisms to shut down histone mRNA biosynthesis. Moreover, I have shown that the SLBP coding sequence is sufficient to induce low translational efficiency of SLBP mRNA as a regulation to keep the SLBP protein level low at early G1. I further showed that at some point in early G1, SLBP translation efficiency recovers back to S phase level but protein stability decreases. It is likely that there is then regulated degradation of SLBP limiting SLBP level until next G1/S.

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