The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication-dependent histone mRNA.

Junho Choe,Sang Ho Ahn,Yoon Ki Kim

doi:10.1093/nar/gku610

Abstract

Histone biogenesis is tightly controlled at multiple steps to maintain the balance between the amounts of DNA and histone protein during the cell cycle. In particular, translation and degradation of replication-dependent histone mRNAs are coordinately regulated. However, the underlying molecular mechanisms remain elusive. Here, we investigate remodeling of stem-loop binding protein (SLBP)-containing histone mRNPs occurring during the switch from the actively translating mode to the degradation mode. The interaction between a CBP80/20-dependent translation initiation factor (CTIF) and SLBP, which is important for efficient histone mRNA translation, is disrupted upon the inhibition of DNA replication or at the end of S phase. This disruption is mediated by competition between CTIF and UPF1 for SLBP binding. Further characterizations reveal hyperphosphorylation of UPF1 by activated ATR and DNA-dependent protein kinase upon the inhibition of DNA replication interacts with SLBP more strongly, promoting the release of CTIF and eIF3 from SLBP-containing histone mRNP. In addition, hyperphosphorylated UPF1 recruits PNRC2 and SMG5, triggering decapping followed by 5′-to-3′ degradation of histone mRNAs. The collective observations suggest that both inhibition of translation and recruitment of mRNA degradation machinery during histone mRNA degradation are tightly coupled and coordinately regulated by UPF1 phosphorylation.

Highlights

In mammals, two different types of cap-binding proteins initiate translation in the cytoplasm (1)
Previous reports showed that rapid degradation of histone mRNAs requires translation promoted by stem-loop binding protein (SLBP) (42–44) and that SLBP is important for rapid degradation of histone mRNA upon the inhibition of DNA replication or at the end of S phase during cell cycle (19,20)
We showed that rapid degradation of histone mRNA largely takes place during CBC-dependent translation (CT) but not eIF4E-dependent translation (ET) (18)

Summary

Introduction

Two different types of cap-binding proteins initiate translation in the cytoplasm (1). During or after mRNA export, the CBC is replaced by eIF4E in the cytoplasm [i.e. CBC-bound mRNAs are precursors of eIF4E-bound mRNAs (1,2)] Both CBC and eIF4E have a common ability to recruit ribosomes, the mechanisms are quite different. In the case of translation of CBC-bound mRNAs, the cap-bound CBC recruits CBC-dependent translation initiation factor (CTIF), which is an eIF4G-like protein, by direct interaction (3). Our recent data showed that CTIF directly binds to eIF3g (4), which is a component of eIF3 complex This observation suggests that CBP80-CTIF at the 5 -end of mRNA recruits the eIF3 complex that, in turn, recruits the small subunit of ribosome (40S), initiating the first round (or pioneer round) of translation (1,3,5). We will hereafter refer to this as CBC-dependent translation (CT), regardless of the number of translation initiations (3)

Methods

Results

Conclusion