Chromatin-modifying functions of INO80 in the preservation of genomic integrity

描述(申请人提供)：最近的研究进展表明，依赖于ATP的染色质重塑复合体，如进化保守的INO80复合体，对于DMA损伤的修复是必不可少的。然而，正确的DMA损伤反应所必需的INO80复合体的不同染色质修饰活性仍有待阐明。这位候选人的长期目标是发展一项独立的研究事业，专注于染色质修饰复合体在DNA损伤反应途径中的参与，以及它们在通过维持基因组完整性防止疾病进展中的作用。这一应用的研究目标是检验中心假设，即特定的INO80亚基通过调节复合体的染色质修饰活性在不同的DNA损伤反应中发挥关键功能。这项申请的职业发展目标将通过一项结合技术培训、讲习班/研讨会和正规课程的计划在支持性研究环境中实现，这将提高研究和专业技能。一旦这些目标实现，结果将为研究进化保守的染色质重塑复合体在DNA损伤反应途径缺陷引起的疾病中的作用提供基础，如癌症。在强大的初步数据的指导下，这一应用的假设将通过结合创新的体外和体内染色质调制分析的方法追求三个特定目标来检验。这些目的是：1)确定在DNA损伤反应中起作用的INO80亚基，并调节DNA损伤特异性的组蛋白修饰；2)确定DNA损伤相关亚基对INO80复合体染色质修饰的体外贡献；3)在体内确定INO80亚基在特定DNA修复和/或检查点途径中的染色质修饰功能。这项拟议的研究具有重要意义，因为它将从根本上洞察INO80在DNA损伤反应途径中的染色质修饰活性。此外，这些分析与公共卫生有关，因为它们将提供一个平台，以解决INO80在疾病发展中的潜在作用。最终，这些研究将极大地拓宽我们对染色质调制的理解，染色质调制具有保护DNA完整性的功能。癌症的发生是一个多步骤的过程，其中包括几个基因改变的实现，这些改变通常是由于DNA损伤反应途径的中断造成的。这些研究将对自然细胞环境中的DNA损伤反应机制提供更完整的描述。

DESCRIPTION (provided by applicant): Recent research advances reveal that ATP-dependent chromatin-remodeling complexes, such as the evolutionarily-conserved INO80 complex, are essential for the repair of DMA lesions. However, the diverse chromatin-modifying activities of the INO80 complex that are necessary for proper DMA damage responses remain to be elucidated. The long-term goals of this candidate are to develop an independent research career focusing on the involvement of chromatin-modifying complexes in DNA damage response pathways, as well as their role in preventing disease progression through the maintenance of genomic integrity. The research objectives of this application are to test the central hypothesis that specific INO80 subunits contribute to critical functions in diverse DNA damage responses by modulating the chromatin-modifying activity of the complex. The career development objectives of this application will be achieved in supportive research environments through a plan that combines technical training, workshops/seminars, and formal courses, which will enhance research and professional skills. Once these objectives are accomplished, the results will provide the foundation to investigate the role of evolutionarily-conserved chromatin-remodeling complexes in disorders caused by defects in DNA damage response pathways, such as cancer. Guided by strong preliminary data, the hypothesis of this application will be tested by pursuing three specific aims through an approach that combines innovative in vitro and in vivo chromatin modulation analyses. These aims are:1) Identify INO80 subunits that function in DNA damage responses and modulate DNA damage- specific histone modifications; 2) Characterize the in vitro chromatin-modifying contributions of DNA damage-related subunits to the INO80 complex; 3) Determine the in vivo chromatin-modifying function of INO80 subunits in specific DNA repair and/or checkpoint pathways. The proposed research is significant because it will present fundamental insight into the chromatin-modifying activities of INO80 in DNA damage response pathways. Furthermore, these analyses are relevant to public health because they will provide a platform to address the potential role of INO80 in the development of disease. Ultimately, these studies will dramatically broaden our understanding of chromatin modulation that functions to preserve DNA integrity. Cancer development occurs through a multi-step process that involves the attainment of several genetic alterations, which often result from disruptions in DNA damage response pathways. These studies will provide a more complete depiction of DNA damage response mechanisms within the natural cellular environment.