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

Abstract

ABSTRACTHuman LUC7 family proteins associate with the U1 small nuclear ribonucleoprotein (snRNP) complex. Mutation or deletion ofLUC7L2is associated with myeloid neoplasms, and depletion ofLUC7L2alters cellular metabolism. Here, we describe distinctive 5’ splice site (5’SS) features of exons impacted by each of the three human LUC7s. We find thatLUC7L2andLUC7Lenhance splicing of “right-handed” 5’SS with stronger consensus matching on the intron side of the near-invariant /GU, whileLUC7L3preferentially 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 ofLUC7L3andLUC7L2subfamilies occurred prior to the divergence of plants from animals/fungi, and suggests that loss of theLUC7L3subfamily from the fungal lineage contributed to the predominance of right-handed 5’SS in fungi.