3′ Processing of Animal Replication‐Dependent Histone mRNAs

Each time a eucaryotic cell divides, it replicates its DNA and packages the DNA into chormatin. Large amounts of all five histone proteins are co-ordinately synthesized to assemble the newly replicated chromatin. The metazoan replication-dependent (RD) histone mRNAs differ from all other cellular mRNAs. They are not polyadenylated, but end instead in a conserved stem-loop (SL). The genes encoding all five RD-histone mRNAs are clustered, and localized to a subdomain of the nucleus, the histone locus body (HLB). Factors required for transcription and 3' processing are concentrated in the HLB, allowing coordinate expression of the five histone mRNAs, which are synthesized inside the HLB. Since RD-histone genes lack introns, capping and 3' end formation are the only processing reactions required for their biosynthesis. A set of factors involved only in histone mRNA metabolism; NPAT, FLASH, U7 snRNP, and SLBP are required for synthesis of histone mRNAs. The HLB is present throughout the cell cycle. Histone mRNA expression is restricted to S-phase by phosphorylation of NPAT by cyclin E/cdk2. Like cleavage/polyadenylation, histone pre-mRNA processing requires recognition of a 5' signal, the SL, by SLBP, and a 3' signal, the histone downstream element (HDE) by U7 snRNP, with cleavage occurring between them. A subcomplex of CPSF, the cleavage module for cleavage/polyadenylation, is a component of the active U7 snRNP, which assembles in the HLB only in S-phase. CPSF73 catalyzes the cleavage of the nascent transcript to produce mature histone mRNA.