Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail

Abstract

The canonical histone proteins are encoded by replication-dependent genes and must rapidly reach high levels of expression during S phase. In metazoans the genes that encode these proteins produce mRNAs that, instead of being polyadenylated, contain a unique 3' end structure. By contrast, the synthesis of the variant, replication-independent histones, which are encoded by polyadenylated mRNAs, persists outside of S phase. Accurate positioning of both histone types in chromatin is essential for proper transcriptional regulation, the demarcation of heterochromatic boundaries and the epigenetic inheritance of gene expression patterns. Recent results suggest that the coordinated synthesis of replication-dependent and variant histone mRNAs is achieved by signals that affect formation of the 3' end of the replication-dependent histone mRNAs.Histones are the primary protein component of chromatin. Although they were initially thought to be mainly involved in chromosomal DNA packaging in eukaryotes, it is now recognized that they also have a crucial role in regulating gene expression. Histones can be extensively modified after translation and these modifications play an important part in regulating gene expression. They are constantly being shifted, modified, evicted and re-deposited as chromatin is continually remodelled (reviewed in REF. 1 ). Thus, the cell must carefully coordinate the replication of DNA, the synthesis of an estimated 10 8 molecules of each histone type in mammalian cells and the rapid deposition of new and old histones to reform chromatin during each relatively short S phase 2,3 .In metazoans the bulk of the histone proteins, defined here as the canonical histone proteins, are encoded by a family of replication-dependent histone genes. Their mRNAs are the only known cellular non-polyadenylated mRNAs in eukaryotes 4 . These genes encode all four core histones -H2A, H2B, H3 and H4 -which make up the nucleosome, and the linker H1 histones, which are found between nucleosomes. In place of a poly(A) tail, replicationdependent histone mRNAs end in a 3′ stem-loop sequence that is crucial in their regulation (FIG. 1a), and is formed by endonu-cleolytic cleavage of the pre-mRNA (FIG. 1b). This novel 3′ end results in the requirement for a distinct set of factors for metabolism and regulation of these histone mRNAs. These mRNAs must be expressed rapidly at the beginning of S phase and must persist at high levels throughout S phase to coincide with the replication of DNA. They are destroyed at the conclusion of S phase or rapidly during S phase if DNA replication is halted.In addition to the canonical histones, there are several variant histones whose synthesis is not cell-cycle-regulated and whose mRNAs are polyadenylated and expressed throughout the cell cycle (replication-independent histone mRNAs). These histones include the H3.3 and Correspondence to W.F.M.

Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

“…Histone protein synthesis is regulated both transcriptionally and post-transcriptionally and is essential for the proper packaging of newly synthesized DNA into chromatin during S phase (Marzluff et al, 2008). Unlike most RNA polymerase II transcribed mRNAs, replication-dependent histone mRNAs are not polyadenylated but instead end in a conserved 3 0 stem-loop structure, which is recognized and cleaved by the stem-loopbinding protein and the U7 snRNP complexes, respectively (Marzluff et al, 2008).…”

“…Unlike most RNA polymerase II transcribed mRNAs, replication-dependent histone mRNAs are not polyadenylated but instead end in a conserved 3 0 stem-loop structure, which is recognized and cleaved by the stem-loopbinding protein and the U7 snRNP complexes, respectively (Marzluff et al, 2008). It is surprising that the loss of normal histone pre-mRNA processing can result in the production of polyadenylated mRNAs from the replication-dependent histone genes (Narita et al, 2007;Wagner et al, 2007).…”

Réponse aux dommages à l’ADN durant l’embryogenèse

“…Chez les eucaryotes supérieurs, ces ARNm ont la particularité d'être non polyadénylés à leur extré-mité 3' et de contenir une structure en tige-boucle hautement conservée dans leur région 3' non traduite [11]. Cette dernière représente un site de liaison pour une protéine désignée SLBP, pour stem loop binding protein, un régulateur très spécifique des ARNm d'histones [12]. Il a été démontré, à la fois chez la drosophile et l'humain, que SLBP est importante pour la maturation, l'export nucléaire et la traduction cytoplasmique des ARNm codant pour les histones [12].…”

“…Cette dernière représente un site de liaison pour une protéine désignée SLBP, pour stem loop binding protein, un régulateur très spécifique des ARNm d'histones [12]. Il a été démontré, à la fois chez la drosophile et l'humain, que SLBP est importante pour la maturation, l'export nucléaire et la traduction cytoplasmique des ARNm codant pour les histones [12]. Par des études de structure-fonction in vivo impliquant l'expression d'ARNm chimériques, nous avons pu montrer que la structure tige-boucle des histones était suffisante pour assurer la rétention de ces ARNm dans le noyau en réponse à un stress [11].…”

Nucleosome assembly and epigenetic inheritance

“…As a result of DNA polymerase passage, the structure of paternal nucleosomes (for example, the intra-and inter-nucleosome combination of histone modifications) is disrupted; old histones should be reorganized on newly synthesized DNA. At the same time, canonical histones are produced tightly coupling to DNA synthesis (Marzluff et al, 2008), fulfilling the gaps among parental histones. Therefore, pre-existing marks are diluted due to incorporation of new histones.…”