FIGURE 10-15 Model for cleavage and polyadenylation of pre-mRNAs in mammalian cells. Cleavage and polyadenylation specificity factor (CPSF) binds to the upstream AAUAAA polyadenylation signal. CStF interacts with a downstream GU- or U-rich sequence and with bound CPSF, forming a loop in the RNA; binding of CFI and CFII helps stabilize the complex. Binding of poly(A) polymerase (PAP) then stimulates cleavage at a poly(A) cleavage site, which usually is 15–30 nucleotides 3′ of the upstream polyadenylation signal. The cleavage factors are released, as is the downstream RNA cleavage product, which is rapidly degraded. Bound PAP then adds about 12 A residues at a slow rate to the 3′-hydroxyl group generated by the cleavage reaction. Binding of nuclear poly(A)-binding protein (PABPN1) to the initial short poly(A) tail accelerates the rate of addition by PAP. After 200–250 A residues have been added, PABPN1 signals PAP to stop polymerization.