Human LUC7 proteins impact splicing of two major subclasses of 5’ splice sites

Human LUC7 family proteins associate with the U1 small nuclear ribonucleoprotein (snRNP) complex. Mutation or deletion of LUC7L2 is associated with myeloid neoplasms, and depletion of LUC7L2 alters cellular metabolism. Here, we describe distinctive 5’ splice site (5’SS) features of exons impacted by each of the three human LUC7s. We find that LUC7L2 and LUC7L enhance splicing of “right-handed” 5’SS with stronger consensus matching on the intron side of the near-invariant /GU, while LUC7L3 preferentially enhances splicing of “left-handed” 5’SS with stronger consensus matching on the exon side of the splice junction. Specificity for right- or left-handed 5’SS is conferred by the distinct structured N-terminal domains of LUC7L2 and LUC7L3. Evolutionary analysis shows that divergence of LUC7L3 and LUC7L2 subfamilies occurred prior to the divergence of plants from animals/fungi, and suggests that loss of the LUC7L3 subfamily from the fungal lineage contributed to the predominance of right-handed 5’SS in fungi.