Kenny Connor J, McGurk Michael P, Schüler Sandra, Cordero Aidan, Laubinger Sascha, Burge Christopher B
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Institute of Biology, Department of Genetics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Nat Commun. 2025 Feb 20;16(1):1574. doi: 10.1038/s41467-025-56577-4.
Mutation or deletion of the U1 snRNP-associated factor LUC7L2 is associated with myeloid neoplasms, and knockout of LUC7L2 alters cellular metabolism. Here, we show that members of the LUC7 protein family differentially regulate two major classes of 5' splice sites (5'SS) and broadly regulate mRNA splicing in both human cell lines and leukemias with LUC7L2 copy number variation. We describe distinctive 5'SS features of exons impacted by the three human LUC7 paralogs: 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 enhances splicing of "left-handed" 5'SS with stronger consensus matching upstream of the /GU. We validated our model of sequence-specific 5'SS regulation both by mutating splice sites and swapping domains between human LUC7 proteins. Evolutionary analysis indicates that the LUC7L2/LUC7L3 subfamilies evolved before the split between animals and plants. Analysis of Arabidopsis thaliana mutants confirmed that plant LUC7 orthologs possess similar specificity to their human counterparts, indicating that 5'SS regulation by LUC7 proteins is highly conserved.
与U1 snRNP相关的因子LUC7L2的突变或缺失与髓系肿瘤相关，并且LUC7L2的敲除会改变细胞代谢。在此，我们表明LUC7蛋白家族成员差异调节两类主要的5'剪接位点（5'SS），并在具有LUC7L2拷贝数变异的人类细胞系和白血病中广泛调节mRNA剪接。我们描述了受三个人类LUC7旁系同源物影响的外显子的独特5'SS特征：LUC7L2和LUC7L增强“右手”5'SS的剪接，在近乎不变的/GU的内含子侧具有更强的共有序列匹配，而LUC7L3增强“左手”5'SS的剪接，在/GU上游具有更强的共有序列匹配。我们通过突变剪接位点和在人类LUC7蛋白之间交换结构域，验证了我们的序列特异性5'SS调节模型。进化分析表明，LUC7L2/LUC7L3亚家族在动植物分化之前就已进化。对拟南芥突变体的分析证实，植物LUC7直系同源物与其人类对应物具有相似的特异性，表明LUC7蛋白对5'SS的调节高度保守。
