Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms

• Published in: Cell reports (Cambridge) 2021-04, Vol.35 (2), p.108989-108989, Article 108989
• Main Authors: Daniels, Noah J., Hershberger, Courtney E., Gu, Xiaorong, Schueger, Caroline, DiPasquale, William M., Brick, Jonathan, Saunthararajah, Yogen, Maciejewski, Jaroslaw P., Padgett, Richard A.
• Format: Article
• Language: English
• Subjects: 5′ splice site; alternative splicing; Base Sequence; Exons; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Introns; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; LUC7L; LUC7L2; LUC7L3; Mutation; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; myeloid neoplasms; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ribonucleoprotein, U1 Small Nuclear - genetics; Ribonucleoprotein, U1 Small Nuclear - metabolism; RNA Splicing; RNA, Small Nuclear - genetics; RNA, Small Nuclear - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction; Spliceosomes
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108989

Vertebrates have evolved three paralogs, termed LUC7L, LUC7L2, and LUC7L3, of the essential yeast U1 small nuclear RNA (snRNA)-associated splicing factor Luc7p. We investigated the mechanistic and regulatory functions of these putative splicing factors, of which one (LUC7L2) is mutated or deleted in myeloid neoplasms. Protein interaction data show that all three proteins bind similar core but distinct regulatory splicing factors, probably mediated through their divergent arginine-serine-rich domains, which are not present in Luc7p. Knockdown of each factor reveals mostly unique sets of significantly dysregulated alternative splicing events dependent on their binding locations, which are largely non-overlapping. Notably, knockdown of LUC7L2 alone significantly upregulates the expression of multiple spliceosomal factors and downregulates glycolysis genes, possibly contributing to disease pathogenesis. RNA binding studies reveal that LUC7L2 and LUC7L3 crosslink to weak 5′ splice sites and to the 5′ end of U1 snRNA, establishing an evolutionarily conserved role in 5′ splice site selection. [Display omitted] •LUC7-like proteins are U1 snRNP components and alternative splicing regulators•LUC7L2 and LUC7L3 share an evolutionarily conserved role in 5′ splice site selection•LUC7-like proteins bind distinct factors regulating unique alternative splicing events•Loss of LUC7L2 alters spliceosome and glycolytic genes that may contribute to disease Mammals have three paralogs of the yeast pre-mRNA splicing factor Luc7p, termed LUC7L, LUC7L2, and LUC7L3, of which one (LUC7L2) is mutated in myeloid neoplasms. Daniels et al. provide functional characterizations of these spliceosomal proteins and elucidation of their distinct roles in alternative splicing and in potential disease pathogenesis.