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

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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.