Summary of complex regulatory interactions that govern biogenesis of the mir-144/451 cluster. (A) mir-451 has a very short stem and small terminal loop, rendering it a suboptimal substrate of the nuclear Microprocessor complex (Drosha + 2DGCR8). (B) Instead, it requires assistance from its operon neighbor mir-144 for effective recruitment and/or cleavage by Microprocessor. Efficient nuclear mir-451 biogenesis requires the accessory factor ERH. The requirement of SAFB proteins, recently implicated in suboptimal miRNA biogenesis at clusters, is unknown. (C) The short hairpin of mir-451 escapes Dicer cleavage but can load directly into Ago effector proteins. Association with non-slicing effectors (Ago1/3/4) is a dead-end path. If pre-mir-451 associates with Ago2, it can be cleaved on the 3′ arm and then further resected by PARN nuclease to yield mature miR-451. (D) pre-mir-144 presents a suboptimal Dicer substrate, on account of its slightly short stem and location of Dicer cleavage site within an asymmetric internal loop. Its terminal loop contains a recognition sequence for ILF3 (NF90/NF110) in complex with ILF2 (NF45), which can recruit the Dicer cofactor TRBP. We hypothesize the ILF3 complex remodels the apical stem region into a form that is competent for Dicer cleavage. In the erythroid lineage, one of the targets of mature miR-144-3p is Dicer itself, which is proposed to lead to downregulation of canonical miRNAs and permit upregulation of Dicer-independent miR-451.
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