Lee Amanda R, Tangiyan Anna, Singh Isha, Choi Peter S
Department of Pathology & Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2025 May 14;21(5):e1011685. doi: 10.1371/journal.pgen.1011685. eCollection 2025 May.
Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other's loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A. We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B, we discover that a subset of cancer cell lines are highly TRA2A-dependent. Upon TRA2A depletion, these cell lines exhibit a lack of paralog buffering specifically on shared splicing targets, leading to defects in mitosis and cell death. Notably, TRA2B overexpression rescues both the aberrant splicing and lethality associated with TRA2A loss, indicating that paralog compensation is dosage-sensitive. Together, these findings reveal a complex dosage-dependent relationship between paralogous splicing factors, and highlight how dysfunctional paralog buffering can create a selective dependency in cancer.
旁系同源基因常常表现出功能冗余，使它们能够有效地相互补偿对方的缺失。然而，这种缓冲机制在癌症中经常被破坏，从而暴露出独特的旁系同源基因特异性脆弱性。在这里，我们确定了对剪接因子TRA2A的选择性依赖性。我们发现TRA2A及其旁系同源基因TRA2B是合成致死伴侣，它们作为可变剪接和组成性剪接的广泛且在很大程度上冗余的激活因子发挥作用。虽然单独缺失TRA2A通常由于TRA2B的补偿而无明显影响，但我们发现一部分癌细胞系高度依赖TRA2A。在TRA2A缺失后，这些细胞系在共享剪接靶点上表现出缺乏旁系同源基因缓冲的情况，导致有丝分裂缺陷和细胞死亡。值得注意的是，TRA2B的过表达挽救了与TRA2A缺失相关的异常剪接和致死性，这表明旁系同源基因补偿对剂量敏感。总之，这些发现揭示了旁系同源剪接因子之间复杂的剂量依赖性关系，并突出了功能失调的旁系同源基因缓冲如何在癌症中产生选择性依赖性。
