Formation of the 3′ end of histone mRNA: Getting closer to the end

Abstract

Nearly all eukaryotic mRNAs end with a poly (A) tail that is added to their 3' end by the ubiquitous cleavage/polyadenylation machinery. The only known exception to this rule are metazoan replication dependent histone mRNAs, which end with a highly conserved stem-loop structure. This distinct 3' end is generated by specialized 3'end processing machinery that cleaves histone pre-mRNAs 4-5 nucleotides downstream of the stem-loop and consists of the U7 small nuclear RNP (snRNP) and number of protein factors. Recently, the U7 snRNP has been shown to contain a unique Sm core that differs from that of the spliceosomal snRNPs, and an essential heat labile processing factor has been identified as symplekin. In addition, cross-linking studies have pinpointed CPSF-73 as the endonuclease, which catalyzes the cleavage reaction. Thus, many of the critical components of the 3' end processing machinery are now identified. Strikingly, this machinery is not as unique as initially thought but contains a number of factors involved in cleavage/polyadenylation, suggesting that the two mechanisms have a common evolutionary origin. The greatest challenge that lies ahead is to determine how all these factors interact with each other to form a catalytically competent processing complex capable of cleaving histone pre-mRNAs.

Transcription termination by nuclear RNA polymerases

“…The 39-ends of histone mRNAs are generated by endonucleolytic cleavage 39 to a dinucleotide CA, positioned downstream from a conserved stem-loop and upstream of a purine-rich histone downstream element (HDE), which is recognized by base-pairing with the 59-end of the U7 snRNA (Schaufele et al 1986;Bond et al 1991; for review, see Dominski and Marzluff 2007). Interestingly, like polyadenylated mRNAs, cleavage is most likely performed by CPSF-73 (Dominski et al 2005a;Yang et al 2009).…”

The Y3** ncRNA promotes the 3′ end processing of histone mRNAs

“…In addition, cleavage 3 ′ to the SL essentially relies on the CPSF CstF-64 (Yang et al 2013) and is catalyzed by CPSF3 (Dominski et al 2005). Correctly processed replication-dependent histone mRNAs lack a poly(A) tail, but aberrant polyadenylation occurs upon misprocessing (Dominski and Marzluff 2007;Marzluff et al 2008;Pirngruber et al 2009). …”

A Conserved Interaction That Is Essential for the Biogenesis of Histone Locus Bodies

“…Transcription of animal replication-dependent histone genes gives rise to intronless mRNA precursors (pre-mRNAs) that undergo a specialized 3Ј end processing reaction to form mature histone mRNAs (1)(2)(3). In this reaction, histone pre-mRNAs are cleaved downstream of a highly conserved stem-loop structure, and the upstream cleavage product is not polyadenylated.…”

“…In this reaction, histone pre-mRNAs are cleaved downstream of a highly conserved stem-loop structure, and the upstream cleavage product is not polyadenylated. Cleavage of histone pre-mRNAs requires the stem-loop binding protein (SLBP), 2 which tightly interacts with the upstream stem-loop (4) and the U7 snRNP, which binds to the histone downstream element (HDE) located 3Ј to the cleavage site (2). SLBP remains bound to the stem-loop following processing and assists mature histone mRNA on its way to the cytoplasm, where it stimulates translation of histone mRNAs into histone proteins (3).…”