已有报道证实增殖细胞核抗原(PCNA)能够与多种蛋白质发生相互作用，参与DNA复制和修复等多种生命过程。然而，与PCNA相互作用的蛋白能否影响PCNA自身的稳定性这方面的研究却较少。我们的研究发现PCNA能够与MutT相关蛋白家族的一个新成员MTH2(MutT homolog2)发生相互作用从而影响PCNA自身的稳定性。首先，我们发现在人的一些癌症细胞系以及人的成纤维细胞系中，PCNA和MTH2存在于同一个复合物中；进一步证明PCNA与MTH2在体外存在直接的相互作用，并且确定了它们相互作用的片段。随后在PCNA-MTH2相互作用机制的研究中，我们惊奇地发现紫外线能够通过诱导PCNA的乙酰化导致PCNA-MTH2复合物解离，以及启动PCNA的降解。接下来为了探究PCNA-MTH2复合物解离和PCNA降解之间的联系，我们用MTH2 RNA干扰实验模拟紫外线诱导的PCNA解离状态，从而检测PCNA半衰期的变化。结果证明在MTH2 RNAi的细胞中PCNA的半衰期明显缩短，PCNA的降解速度明显加快。因此，我们推断在生理状态下PCNA-MTH2复合物存在的意义是增强PCNA的稳定性，保护PCNA不被降解，而紫外线照射导致的两蛋白解离会加快PCNA的降解速度。此外，PCNA的降解进一步增强了紫外线引起的DNA合成抑制和细胞周期阻滞。我们的课题揭示了PCNA和MTH2相互作用的机制，即PCNA通过与MTH2相互作用影响PCNA的稳定性。 关键词：基白质-蛋白质相互作用，蛋白质降解，蛋白质翻译后装饰，PCNA， MutT homolog2

 Proliferating cell nuclear antigen (PCNA) has been demonstrated to interact with multiple proteins involved in several metabolic pathways such as DNA replication and repair. However, there have been fewer reports about whether these PCNA-binding proteins influence stability of PCNA. Here, we observed a physical interaction between PCNA and MutT homolog2 (MTH2), a new member of the MutT-related proteins that hydrolyzes 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP). In several unstressed human cancer cell lines and in normal human fibroblast cells, PCNA and MTH2 formed a complex and their mutual binding fragments were confirmed. It was intriguing that PCNA and MTH2 were dissociated dependent on acetylation of PCNA, which in turn induced degradation of PCNA in response to UV irradiation, but not in response to other forms of DNA damaging stress. To further explore the link between dissociation of PCNA-MTH2 and degradation of PCNA, RNAi against MTH2 was performed to mimic the dissociated status of PCNA to evaluate changes in the half-life of PCNA. Knockdown of MTH2 significantly promoted degradation of PCNA, suggesting that the physiological interaction of PCNA-MTH2 may confer protection from degradation for PCNA, whereas UV irradiation accelerates PCNA degradation by inducing dissociation of PCNA-MTH2. Moreover, due to degradation of PCNA, UV-induced inhibition of DNA synthesis or cell cycle progression was enhanced. Collectively, our data demonstrate for the first time that PCNA is protected by this newly identified partner molecule MTH2, which is related to DNA synthesis and cell cycle progression. [Keywords]: protein-protein interaction, protein degradation, post-translational modification, PCNA, MutT homolog2