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: 7781702
• 负责人: CHENGTAO HER
• 金额: $ 27.4万
• 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/7781702
• 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; Human; Inherited; Ionizing radiation; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Meiosis; 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，更好地理解DNA双链断裂（DSB）修复和细胞对DNA DSB诱导剂（即电离辐射和化疗药物）的反应的机制基础对于破译癌症发展的分子基础以及为开发新的抗癌策略提供基础至关重要。最近的实验表明，hMSH 5和各种蛋白质相互作用伙伴之间的相互作用是至关重要的参与DNA损伤的反应和修复。特别是，hMSH 5和hMSH 4之间的相互作用提供了一个基础，形成一个特定的异源复合物，能够结合到霍利迪连接中间体，暗示其在重组修复的潜在功能。此外，hMSH 5的物理和功能相互作用的c-Abl，后者是一个关键的酪氨酸激酶在细胞周期停滞，DNA修复和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hMSH 5和hMSH 4蛋白的局部募集，并且DSB诱导的hMSH 5负载依赖于功能性hMRE 11和hRad 51蛋白。我们最近的研究表明，c-Abl激酶的激活可以通过hMSH 5相互作用来调节，其中这种相互作用促进c-Abl激酶活性的激活并导致hMSH 5酪氨酸磷酸化。这些结果提示hMSH 5在有丝分裂DNA重组修复和细胞对DNA损伤的反应中起重要作用，提示hMSH 5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著影响正常细胞周期进程以及对拟放射性癌症治疗的细胞反应。 本研究的总体目标是通过一系列系统和全面的实验探索，阐明hMSH 5在重组修复和细胞对DNA损伤剂反应中的分子机制。该研究计划的长期目标是阐明与不同类型的DNA重组修复及其与DNA损伤反应途径的联系有关的分子机制。这些研究的结果将为开发更有效的治疗手段和新的癌症治疗分子靶点提供基础。 公共卫生相关性： 预计这些研究的结果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新方法的跳板。