Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation

Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice.癌症的常见特征包括细胞周期进程失调与基因组不稳定性的产生。在肿瘤组织中，G1细胞周期检验点（G1 cell cycle checkpoint）的诱导功能通常缺失，这会增强细胞对功能性G2/M细胞周期检验点（G2/M cell cycle checkpoint）的依赖，使细胞可借助该检验点阻止携带受损DNA的细胞进入有丝分裂阶段，从而避免引入潜在的异常遗传变异。临床中采用电离辐射（ionizing radiation，IR）治疗肿瘤，正是依托肿瘤细胞对G2/M检验点的这种依赖特性，因此鉴定调控该过程的分子因子，可为优化这一临床广泛应用的癌症治疗手段提供关键生物标志物。含亮氨酸拉链与ICAT结构域的蛋白（Leucine zipper and ICAT domain containing，LZIC）的表达下调，与电离辐射诱导的肿瘤发生密切相关；尽管LZIC在物种间高度保守，但其确切的分子功能至今仍未明确。本研究证实，LZIC敲除（knockout，KO）细胞系经电离辐射处理后，其G2/M细胞周期检验点的调控出现失调。此外，研究发现LZIC缺陷细胞可正常激活G1检验点与早期G2/M检验点，但在电离辐射暴露后无法维持晚期G2/M检验点的功能，具体而言，该调控缺陷发生在PIKK信号通路的下游。LZIC敲除细胞表现出严重的非整倍性，提示其存在基因组不稳定性；此外，对癌症患者数据库数据的分析显示，在多种癌症中，LZIC的表达水平与患者不良预后存在显著相关性。本研究结果表明，LZIC在细胞对电离辐射的应答过程中发挥功能性作用，其表达水平可作为临床癌症实践中患者分层的生物标志物。