ATP-dependent chromatin-remodeling complexes, such as the evolutionarily-conserved INO80 complex, are essential for the maintenance of genomic integrity. However, the diverse INO80 chromatin-modifying activities that are necessary for proper DNA damage responses remain to be elucidated. Our long-term goal is to delineate 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 overall objective of this proposal, which is an initial step to the achievement of our long-term goal, utilizes the yeast model system to determine the specific involvement ofthe INO80 chromatin-remodeling complex in different functions of DNA damage response pathways. Our central hypothesis is that specific INO80 subunits contribute to critical functions in diverse genome maintenance pathways by modulating the chromatin-modifying activities of the complex. 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, this hypothesis will be tested through an integrated experimental approach that utilizes proteomics, high-throughput genetic screens, genome-wide nucleosome mapping, and biochemical assays. We propose to test our central hypothesis and accomplish the objectives ofthis application by pursuing the following specific aims: 1) Characterize INO80 subunits that function in DNA damage responses and modulate DNA damage-specific chromatin substrates;2) Delineate the in vitro chromatin-modifying contributions of DNA damage-related subunits to the activity INO80 complex;3) Determine the in vivo chromatin-modifying function of INO80 subunits in specific DNA damage response pathways. These analyses are relevant to public heaith 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.

Public Health Relevance

Cancer development evolves through a multi-step process that provides cells with a proliferative and/or survival advantage through the attainment of multiple genetic alterations, which are often caused by disruptions in pathways that maintain genomic integrity. These studies will provide insight into the mechanisms within the natural cellular environment that prevent the accumulation of genomic perturbation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Carter, Anthony D
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Stanford University
Schools of Arts and Sciences
United States
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Yao, Wei; King, Devin A; Beckwith, Sean L et al. (2016) The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation. Mol Cell Biol 36:979-91
Yao, Wei; Beckwith, Sean L; Zheng, Tina et al. (2015) Assembly of the Arp5 (Actin-related Protein) Subunit Involved in Distinct INO80 Chromatin Remodeling Activities. J Biol Chem 290:25700-9
Martín, Glòria Mas; King, Devin A; Garcia-Nieto, Pablo E et al. (2014) Transcriptome profiling of Set5 and Set1 methyltransferases: Tools for visualization of gene expression. Genom Data 2:216-218
Martín, Glòria Mas; King, Devin A; Green, Erin M et al. (2014) Set5 and Set1 cooperate to repress gene expression at telomeres and retrotransposons. Epigenetics 9:513-22