Molecular Biology

Finely Balanced Registers

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Science  20 Feb 2009:
Vol. 323, Issue 5917, pp. 985
DOI: 10.1126/science.323.5917.985a

Many genes are interrupted by noncoding introns that must be precisely excised from the RNA molecules transcribed from the gene. In the first step of the splicing reaction, a large RNA-protein splicing machine recognizes the 5′ end of most introns via the complementarity of this region to one of the spliceosome components, the U1 RNA. Yet other 5′ splice sites show little complementarity to the canonical U1 sequence and are nonetheless efficiently and accurately spliced by the very same machine.

In puzzling over this conundrum, Roca and Krainer noticed that a subset of these atypical 5′ splice sites did have a sequence that could form a base-paired region with the U1 sequence, but only if shifted one base downstream of the normal 5′ splice site (the +1 register). Mutating one of these atypical 5′ splice sites to improve its complementarity to the U1 RNA in the canonical register resulted in aberrant, rather than improved, splicing. Furthermore, mutations in the +1, but not canonical, register of the U1 RNA that restored base pairing with the mutated atypical 5′ splice sites could rescue the splicing defects. Understanding that the U1 RNA can recognize two subsets of 5′ splice sites in two registers accounts for the splicing of atypical 5′ splice sites and also explains the deleterious effect of a mutation in the intron of the gene RARS2, which is associated with pontocerebellar hypoplasia. Although the 5′ splice site mutation improves complementarity with the canonical U1 register, it weakens base pairing in the +1 register, and it is this imbalance that probably causes the exon skipping seen in the disease. — GR

Nat. Struct. Molec. Biol. 16, 176 (2009).

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