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

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)修复和细胞对DNA双链断裂诱导剂(即电离辐射和化疗)的反应的机制基础，对于破译癌症发生的分子基础以及为开发新的抗癌策略提供基础是至关重要的。最近的实验表明，hMSH5与各种蛋白质相互作用伙伴之间的相互作用在DNA损伤反应和修复中起关键作用。特别是，hMSH5和hMSH4之间的相互作用为形成能够与Holliday连接中间体结合的特定杂化复合体提供了基础，暗示了它们在重组修复中的潜在功能。此外，hMSH5在物理和功能上与c-Abl相互作用；c-Abl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触发了内源性hMSH5和hMSH4蛋白的局部招募，并且DSB诱导的hMSH5负载依赖于功能上的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相互作用来调节，这种相互作用促进了c-Abl激酶活性的激活，并导致hMSH5酪氨酸磷酸化。综上所述，我们的结果提示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，暗示hMSH5在DNA修复中的作用与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的细胞周期进程以及细胞对仿射线癌症治疗的反应。我们这项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损伤剂反应中的作用的分子机制。这项研究的长期目标是阐明不同类型DNA重组修复的分子机制及其与DNA损伤反应途径的联系。这些研究结果将为开发更有效的治疗手段和癌症治疗的新分子靶点提供基础。

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.