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

描述（由申请人提供）：最近的研究进展表明，ATP依赖性染色质重塑复合物，如进化上保守的INO 80复合物，对DMA损伤的修复至关重要。然而，不同的染色质修饰活动的INO 80复杂的是必要的适当的DMA损伤反应仍有待阐明。这位候选人的长期目标是发展一个独立的研究生涯，专注于染色质修饰复合物在DNA损伤反应途径中的参与，以及它们通过维护基因组完整性在预防疾病进展中的作用。本申请的研究目标是测试中心假设，即特定的INO 80亚基通过调节复合物的染色质修饰活性，在不同的DNA损伤反应中发挥关键作用。该应用程序的职业发展目标将通过一个计划，结合技术培训，讲习班/研讨会和正式课程，这将提高研究和专业技能，在支持性的研究环境中实现。一旦这些目标得以实现，这些结果将为研究进化保守的染色质重塑复合物在DNA损伤反应途径缺陷引起的疾病（如癌症）中的作用提供基础。在强有力的初步数据的指导下，本申请的假设将通过结合创新的体外和体内染色质调节分析的方法，通过追求三个特定目标进行测试。这些目的是：1）鉴定在DNA损伤应答中起作用并调节DNA损伤特异性组蛋白修饰的INO 80亚基; 2）表征DNA损伤相关亚基对INO 80复合物的体外染色质修饰贡献; 3）确定INO 80亚基在特异性DNA修复和/或检查点途径中的体内染色质修饰功能。这项研究具有重要意义，因为它将为INO 80在DNA损伤反应途径中的染色质修饰活性提供基本的见解。此外，这些分析与公共卫生相关，因为它们将提供一个平台来解决INO 80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节的理解，染色质调节的功能是保持DNA的完整性。癌症的发展是通过一个多步骤的过程发生的，该过程涉及几种遗传改变的实现，这些遗传改变通常是由DNA损伤反应途径的中断引起的。这些研究将为自然细胞环境中的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.