Birth and Death of Histone mRNAs

Abstract

In metazoans, histone mRNAs are not polyadenylated but end in a conserved stem-loop. Stem-loop binding protein (SLBP) binds to the stem-loop and is required for all steps in histone mRNA metabolism. The genes for the five histone proteins are linked. A histone locus body (HLB) forms at each histone gene locus. It contains factors essential for transcription and processing of histone mRNAs, and couples transcription and processing. The active form of U7 snRNP contains the HLB component FLASH (FLICE-associated huge protein), the histone cleavage complex (HCC), and a subset of polyadenylation factors including the endonuclease CPSF73. Histone mRNAs are rapidly degraded when DNA replication is inhibited by a 3' to 5' pathway that requires extensive uridylation of mRNA decay intermediates.

Figure 1

A schematic of the life cycle of histone mRNAs and SLBP in mammalian cells. Note that SLBP participates in every part of the histone mRNA life cycle, and is also cell cycle-regulated. Abbreviations: SLBP, stem-loop binding protein; P, phosphorylation; Pol II, polymerase II

Figure 2. Histone genes and the HLB

(A) Organization of the histone genes in the human HIST2 cluster and in Drosophila melanogaster. (B) Model of HLB assembly and changes during the cell cycle in Drosophila. The image shows the merged image of HLBs in every nucleus of the Drosophila syncytial embryo stained with Mxc and FLASH. (C) Staining of HeLa cells with FLASH and Coilin (top) and NPAT and FLASH (bottom). Note that the HLBs are distinct from the Cajal body in these cells [76]. Adapted from Duronio and Marzluff [87]. Abbreviations: HCC, histone cleavage complex; HLB, histone locus body.

Figure 3. Processing of Histone Pre-mRNAs

(Top) Schematic of the histone pre-mRNA processing reaction. (Bottom) Possible forms of U7 snRNP that are present during the cell cycle. The active form (holo-U7) snRNP is present in S-phase. Based on staining of Drosophila HLBs [82], the HCC is not present bound to U7 snRNP in non-dividing cells. We cannot distinguish whether the U7 snRNP and FLASH are separate within the HLB, or whether the U7 snRNP/FLASH complex is present and not able to recruit the HCC. Abbreviations: HCC, histone cleavage complex; HLB, histone locus body.

Figure 4. Uridylation and Degradation of Histone mRNA

After processing the histone mRNA is trimmed by 3′hExo. If trimming proceeds to within 1–2 nt of the stem the mRNA is repaired by TUT7 to the proper length. When DNA replication is inhibited, Upf1 is recruited to the histone mRNA, and 3′hExo can degrade into the stem. When the nuclease stalls the mRNA is then uridylated and degradation can resume. Abbreviations: SLBP, stem-loop binding protein; UTR, untranslated region.

Figure I

Structure of SLBP.