Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
Cell Rep. 2021 Apr 13;35(2):108989. 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.
脊椎动物进化出了三个酵母 U1 小核 RNA（snRNA）相关剪接因子 Luc7p 的直系同源物，分别称为 LUC7L、LUC7L2 和 LUC7L3。我们研究了这些潜在剪接因子的机制和调节功能，其中一个（LUC7L2）在髓系肿瘤中发生突变或缺失。蛋白相互作用数据表明，这三种蛋白均结合相似的核心但不同的调节性剪接因子，可能通过其发散的精氨酸-丝氨酸富含结构域介导，而该结构域在 Luc7p 中不存在。敲低每种因子都会导致大量独特的、显著失调的剪接事件，这取决于它们的结合位置，而这些位置大多是不重叠的。值得注意的是，单独敲低 LUC7L2 会显著上调多个剪接体因子的表达，并下调糖酵解基因，这可能有助于疾病的发病机制。RNA 结合研究表明，LUC7L2 和 LUC7L3 与弱 5' 剪接位点和 U1 snRNA 的 5' 端交联，在 5' 剪接位点选择中发挥保守作用。
