As if on cue, a new study reinforces some ideas I discussed in another essay. This report from Joan Steitz’ lab shows that both CPSF73 and CPSF100 contribute important residues for the endonuclease responsible for maturation of histone mRNAs*. The abstract:
“In eukaryotes, the process of messenger RNA 3′-end formation involves endonucleolytic cleavage of the transcript followed by synthesis of the poly(A) tail. The complex machinery involved in this maturation process contains two proteins of the metallo-beta-lactamase (MBL) superfamily, the 73 and 100 kDa subunits of the cleavage and polyadenylation specificity factor (CPSF). By using an in vitro system to assess point mutations in these two mammalian proteins, we found that conserved residues from the MBL motifs of both polypeptides are required for assembly of the endonuclease activity that cleaves histone pre-mRNAs. This indicates that CPSF73 and CPSF100 act together in the process of maturation of eukaryotic pre-messenger RNAs, similar to other members of the MBL family, RNases Z and J, which function as homodimers.”
The functional and evolutionary implications are fascinating. Of particular note are the possible roles that gene duplication may have played in the origins of the eukaryotic polyadenylation complex (recall that CPSF73 and CPSF100 are themselves related at the sequence level, and are both metallo-beta-lactamase family members), and the functional similarities with bacterial metallo-beta-lactamase nucleases. It is also interesting to see how a shared core (CPSF) has assumed different functions, through interactions with different “accessory factors”. (The notion that U7 and CstF are “accessory factors” is a bit unconventional, to be sure.) And of course, in keeping with one theme of this blog, the implications that this emerging story has for the origins and evolution of irreducibly complex systems are considerable.
Nikolay G Kolev, Therese A Yario, Eleni Benson, Joan A Steitz (2008). Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3′-end maturation EMBO reports, 9 (10), 1013-1018 DOI: 10.1038/embor.2008.146
* astute readers may recall that cell-cycle-regulated histone mRNAs are not polyadenylated. Instead, they have distinctive structures at their 3’ ends, which are formed by a complex that includes the snRNP U7. It turns out that many of the additional proteins that act in concert with U7 are identical to subunits of the polyadenylation complex. CPSF73 and CPSF100 are two of these; the scaffolding protein symplekin is another.