Roles of hMSH5 in DNA recombination and cellular response to anticancer treatmen

hMSH5 在 DNA 重组和细胞抗癌治疗反应中的作用

• 批准号: 8043580
• 负责人: CHENGTAO HER
• 金额: $ 27.77万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043580
• 关键词: ABL1 gene; Affect; Antineoplastic Agents; Apoptosis; Binding; Cell Cycle Arrest; Cell Cycle Progression; Cell Survival; Coupled; Cruciform DNA; DNA; DNA Damage; DNA Double Strand Break; DNA Fingerprinting; DNA Repair; Data; Development; Double Strand Break Repair; Effectiveness; Event; Exposure to; Foundations; Genetic Polymorphism; Genetic Recombination; Genome; Goals; Homologous Gene; Human; Inherited; Ionizing radiation; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Meiosis; Meiotic Recombination; Metabolism; Mismatch Repair; Mitotic; Molecular; Molecular Target; Mutation; Normal Cell; Outcome; Outcome Study; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Protein Family; Protein Tyrosine Kinase; Proteins; Radio; Repetitive Sequence; Research; Role; Series; Site; Testing; Therapeutic; Treatment Efficacy; Tyrosine Phosphorylation; Work; base; c-abl Proto-Oncogenes; cancer cell; cancer therapy; chemotherapeutic agent; design; human disease; improved; innovation; member; novel; programs; public health relevance; recombinational repair; repaired; research study; response

DESCRIPTION (provided by applicant): DNA damage is one of the most important factors in cancer development in humans, and yet it also contributes to the therapeutic efficacy of many anti-cancer drugs. Thus, a better understanding of the mechanistic basis underlying DNA double strand break (DSB) repair and cellular responses to DNA DSB inducing agents (i.e. ionizing radiation and chemotherapeutics) is essential in deciphering the molecular basis underlying cancer development, as well as providing a foundation for developing new anti-cancer strategies. Recent experiments have demonstrated that interplays between hMSH5 and various protein interacting partners are critically involved in DNA damage response and repair. In particular, the interaction between hMSH5 and hMSH4 provided a basis for the formation of a specific heterocomplex that was capable of binding to Holliday junction intermediates, implicating their potential functions in recombinational repair. Furthermore, hMSH5 physically and functionally interacted with c-Abl; the latter is a critical tyrosine kinase playing essential roles in cell cycle arrests, DNA repair, and apoptosis. Our recent preliminary results indicate that DSB triggers local recruitments of endogenous hMSH5 and hMSH4 proteins, and the DSB- induced hMSH5 loading is dependent on functional hMRE11 and hRad51 proteins. Our recent study reveals that the activation of c-Abl kinase can be modulated through hMSH5 interaction, in which this interaction promotes the activation of c-Abl kinase activity and leads to hMSH5 tyrosine phosphorylation. Together, our results suggest important roles of hMSH5 in mitotic DNA recombinational repair and cellular response to DNA damage, implicating that the function of hMSH5 in DNA repair is closely coupled with DNA damage response pathway. It is conceivable that any deviations of such dynamics could significantly affect normal cell cycle progression as well as cellular responses to radiomimetic cancer treatments. The overall objective of our studies outlined in this proposal is to decipher the molecular mechanisms underlying the functions of hMSH5 in recombinational repair and cellular response to DNA damaging agents through a series of systematic and comprehensive experimental explorations. The long- term goal of this research program is to elucidate the molecular mechanisms involved with different types of DNA recombinational repair and their links to DNA damage response pathways. The outcome of these studies will provide a foundation for developing more efficient therapeutic means and novel molecular targets in cancer treatments. PUBLIC HEALTH RELEVANCE: The outcomes of the proposed studies are expected to have a high impact on improving the effectiveness of cancer therapy, and at the same the results of our studies will serve as a springboard for developing new ways to treat cancer.

描述（由申请人提供）： DNA损伤是人类癌症发展中最重要的因素之一，但它也有助于许多抗癌药物的治疗效果。因此，更好地了解 DNA 双链断裂 (DSB) 修复的机制基础以及细胞对 DNA DSB 诱导剂（即电离辐射和化疗）的反应对于破译癌症发展的分子基础并提供基础至关重要开发新的抗癌策略。最近的实验表明，hMSH5 和各种蛋白质相互作用伙伴之间的相互作用对于 DNA 损伤反应和修复至关重要。特别是，hMSH5和hMSH4之间的相互作用为形成能够与霍利迪连接体中间体结合的特定异质复合物提供了基础，暗示它们在重组修复中的潜在功能。此外，hMSH5 在物理上和功能上与 c-Abl 相互作用；后者是一种关键的酪氨酸激酶，在细胞周期停滞、DNA 修复和细胞凋亡中发挥重要作用。我们最近的初步结果表明，DSB 触发内源性 hMSH5 和 hMSH4 蛋白的局部募集，并且 DSB 诱导的 hMSH5 负载依赖于功能性 hMRE11 和 hRad51 蛋白。我们最近的研究表明，c-Abl 激酶的激活可以通过 hMSH5 相互作用进行调节，其中这种相互作用促进 c-Abl 激酶活性的激活并导致 hMSH5 酪氨酸磷酸化。总之，我们的结果表明 hMSH5 在有丝分裂 DNA 重组修复和细胞对 DNA 损伤的反应中发挥重要作用，这表明 hMSH5 在 DNA 修复中的功能与 DNA 损伤反应途径密切相关。可以想象，这种动力学的任何偏差都可能显着影响正常的细胞周期进程以及细胞对放射模拟癌症治疗的反应。 本提案中概述的研究的总体目标是通过一系列系统和全面的实验探索，破译 hMSH5 在重组修复和细胞对 DNA 损伤剂反应中功能的分子机制。该研究计划的长期目标是阐明不同类型 DNA 重组修复所涉及的分子机制及其与 DNA 损伤反应途径的联系。这些研究的结果将为开发更有效的治疗手段和癌症治疗中的新型分子靶点奠定基础。 公共卫生相关性： 拟议研究的结果预计将对提高癌症治疗的有效性产生重大影响，同时我们的研究结果将成为开发治疗癌症的新方法的跳板。