Plk1 gene regulatory network involved in genomic instability

Recently, the dynamics behind the events of genomic instability have gained relevance due to their association with specific genes and cellular mechanisms, which are presented as new and powerful therapeutic alternatives for the disease. Previous studies found the gene Plk1 as a candidate for genomic instability; however, the mechanisms by which the gene and its dysregulation could induce genomic instability events weren’t entirely clear. Therefore, to elucidate the mechanisms, gene circuits, and proteins involved in the genomic instability events promoted by Plk1, a novel approach that involved the reconstruction and modeling of the regulatory network of Plk1 was adopted. The network contains nine processes where Plk1 participates that are involved in maintaining the stability of the genome. Subsequently, mathematical modeling of the regulation network was carried out under a mass action law kinetic approximation to generate a model with 1030 reactions and 716 biological species. The simulations allowed the identification of three interaction circuits between proteins that can potentially induce a genomic instability event as a product of Plk1 dysregulation. Additionally, eight proteins previously associated with genomic instability were identified within the circuits and proposed to amplify the genome instability event. As a novelty, the proteins KIF2C and INCENP are postulated as candidates to participate in the genomic instability process. The information contained herein can be used to feed future models, which are built under similar approaches.近年来，基因组不稳定性（genomic instability）事件背后的调控机制愈发受到学界重视，因其与特定基因及细胞机制密切相关——而这些基因和机制可作为针对该疾病的新型高效治疗靶点。既往研究已将Plk1基因列为基因组不稳定性的候选相关基因，但该基因及其表达失调诱发基因组不稳定性事件的具体分子机制仍未完全阐明。为阐明Plk1介导的基因组不稳定性事件所涉及的分子机制、基因回路（gene circuits）及相关蛋白，本研究采用了一种全新的研究策略：对Plk1的调控网络进行重构与建模。该调控网络共包含9个由Plk1参与、且与基因组稳定性维持相关的生物学过程。随后，本研究基于质量作用定律（mass action law）动力学近似法对该调控网络开展数学建模，最终构建出包含1030个反应及716个生物物种的模型。通过模拟分析，研究团队鉴定出3个蛋白质相互作用回路，这些回路可通过Plk1失调诱发基因组不稳定性事件。此外，研究人员在这些回路中鉴定出8个此前已被证实与基因组不稳定性相关的蛋白质，并提出它们可放大基因组不稳定性事件的发生。本研究的创新之处在于，将KIF2C与INCENP两种蛋白质推定为本研究中参与基因组不稳定性过程的候选因子。本文所披露的研究数据可用于支撑后续采用同类策略构建的相关模型。