化疗药物耐受性是当今肿瘤治疗的难题。研究表明，P53基因突变的NSCLC（非小细胞肺癌）细胞依赖MK2/hnRNPA0信号途径来抵御化疗药物，被激酶MK2磷酸化修饰的hnRNPA0蛋白在转录后层次通过调控编码p27kip1和Gadd45α蛋白的mRNA的稳定性来加强对细胞周期检查点的控制，从而使化疗药物损伤的DNA得到修复。在本课题中，我们拟解析hnRNPA0、hnRNPA0P以及hnRNPA0P-RNA复合物的晶体结构。通过结构分析，明确MK2如何通过磷酸化的方式调控hnRNPA0识别并稳定编码p27kip1/Gadd45α蛋白的mRNA的分子机制。此外，有文献表明hnRNPA0可以和ELAVL1形成蛋白质翻译抑制复合体，结合到靶mRNA的5’UTR上从而抑制蛋白质翻译，在本课题中我们将对该复合体的组装及靶RNA的识别机制进行阐述。

Chemotherapeutic tolerance is a major problem in cancer treatment. Studies show that NSCLC tumors with mutations in P53 are critically dependent on the activity of a post-transcriptional MK2/hnRNPA0 pathway for resistance to chemotherapy. Phosphorylated hnRNPA0 regulates both p27Kip1 and Gadd45α to enforce cell cycle checkpoints, allowing DNA repair and tolerance to chemotherapy. In this project, we determine the crystal structures of hnRNPA0, hnRNPA0P and hnRNPA0P in complex with target RNA. We will elaborate the target RNA recognition mechanism of the phosphorylated hnRNPA0 based on structural information. Combining point mutations and ITC experiments, we will identify the residues vital for hnRNPA0P to recognize target RNA. We will further investigate the effect of hnRNPA0 mutants on the stabilization of the p27kip1/ Gadd45a mRNA and resistance to chemotherapy in vivo. In addition, studies suggest that hnRNPA0 and ELAVL1 could form a translation regulatory system, which binds directly to the 5’UTR region of target mRNA to inhibit the translation. In this project, we will illustrate the mechanisms of complex assembly and target RNA recognition.