Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1

Abstract

Eukaryotic cells coordinately regulate histone and DNA synthesis. In mammalian cells, most of the regulation of histone synthesis occurs post-transcriptionally by regulating the concentrations of histone mRNA. As cells enter S phase, histone mRNA levels increase, and at the end of S phase they are rapidly degraded. Moreover, inhibition of DNA synthesis causes rapid degradation of histone mRNAs. Replication-dependent histone mRNAs are the only metazoan mRNAs that are not polyadenylated. Instead, they end with a conserved stem-loop structure, which is the only cis-acting element required for coupling regulation of histone mRNA half-life with DNA synthesis. Here we show that regulated degradation of histone mRNAs requires Upf1, a key regulator of the nonsense-mediated decay pathway, and ATR, a key regulator of the DNA damage checkpoint pathway activated during replication stress.

Autoregulation of the nonsense-mediated mRNA decay pathway in human cells

“…Such a profound change of histone levels has not been previously noted in microarrays performed by various laboratories in yeast, fly, and human cells (Lelivelt and Culbertson 1999;He et al 2003;Mendell et al 2004;Rehwinkel et al 2005), possibly because these previous studies selectively detected the polyadenylated transcriptome, whereas our exon arrays detect also nonpolyadenylated transcripts due to the use of randomly attaching primers. In contrast to our data, which suggest that UPF1 enhances the expression of histone genes and/or the stability of histone transcripts, UPF1 has previously been implicated in the degradation of histone mRNAs (Kaygun and Marzluff 2005).…”

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

“…39,40 UPF1 also acts in non-NMD decay pathways, such as staufen1 (STAU1)-mediated mRNA decay (SMD) and replication-dependent histone mRNA decay. 41,42 Gene expression profiles of mammalian cells using siRNA-mediated depletion of UPF1 indicated that a significant fraction of cellular transcripts are upregulated, most of which are considered NMD-sensitive transcripts. 24,31,36,43 However, NMD-sensitive changes in abundance are not always accompanied by altered decay rates.…”

“…The regulated degradation of histone mRNAs requires UPF1. 42 Regulation of histone synthesis mostly occurs post-transcriptionally by regulating the concentrations of histone mRNA. unstable in UPF1-depleted cells.…”

The Double Life of UPF1 in RNA and DNA Stability Pathways

“…1,2 Human UPF1 also mediates two RNA decay processes, which are independent of canonical NMD as they do not require UPF2: first, it targets those mRNA molecules that are bound to the RNA binding protein Staufen1 for degradation; 3 second, together with Stem-Loop Binding Protein (SLBP), it promotes degradation of replication-dependent histone mRNAs at the end of S phase and when DNA replication is inhibited. 4 We recently revealed that UPF1 is not only a key player in RNA degradation pathways, but that it is also essential for accomplishing DNA replication during S phase of the cell cycle. 5 DNA replication allows the faithful duplication of chromosomal DNA, which is then equally segregated into two daughter cells following cytokinesis.…”

“…4 However, loss of this function cannot easily explain the early S phase arrest observed in UPF1-depleted cells. Indeed, the cell cycle regulated degradation of replication-dependent histone mRNAs occurs specifically at the end of S phase.…”