The broad, long term goal of the proposed study is to determine, at the molecular level, mechanisms and function of ATP-dependent chromatin remodeling in vivo. ATP-dependent chromatin remodeling factors are highly conserved ATPases that utilize the energy of ATP hydrolysis to alter chromatin structure. Because of their biochemical activities and high abundance, ATP-dependent chromatin remodeling factors can affect a wide variety of DNA- dependent processes, including transcription, DNA replication and DNA damage repair. The importance of physiological roles the chromatin remodeling factors play are highlighted by the fact that many of them are mutated in a variety of human diseases, including cancer. Therefore, elucidating the mechanisms and functions of chromatin remodeling factors will significantly impact not only basic sciences but also medical sciences. In the current funding cycle of this grant, we have made surprising discovery that chromatin remodeling factors regulate transcription of non-coding RNA (ncRNA) and activity of the S phase checkpoint. It has recently become clear that a significant fraction of eukaryotic genomes are transcribed to produce ncRNA. Some of them play critical roles in controlling cell differentiation, gene expression, and cancer development. However, physiological roles of the vast majority of ncRNA are unknown. Moreover, mechanisms to regulate ncRNA transcription are almost entirely unknown. The S phase checkpoint plays essential roles in the maintenance of genome stability. However, how its activity is regulated is not well understood. We will take advantage of our recent findings that highly conserved chromatin remodeling factors regulate ncRNA and the S phase checkpoint activity, and elucidate the underlying mechanisms and biological functions of these regulatory mechanisms.

Public Health Relevance

The S phase checkpoint and non-coding RNA transcripts play critical roles in normal cell growth and their mis-regulation can lead to serious diseases such as cancer. However, how they are regulated remains largely unknown. The goal of our work is to understand the molecular mechanisms by which the S phase checkpoint and non-coding RNA transcription are precisely controlled.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM058465-16
Application #
8710241
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Rodriguez, Jairo; McKnight, Jeffrey N; Tsukiyama, Toshio (2014) Genome-Wide Analysis of Nucleosome Positions, Occupancy, and Accessibility in Yeast: Nucleosome Mapping, High-Resolution Histone ChIP, and NCAM. Curr Protoc Mol Biol 108:21.28.1-21.28.16
Alcid, Eric A; Tsukiyama, Toshio (2014) ATP-dependent chromatin remodeling shapes the long noncoding RNA landscape. Genes Dev 28:2348-60
Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael et al. (2013) DNA looping facilitates targeting of a chromatin remodeling enzyme. Mol Cell 50:93-103
Yadon, Adam N; Tsukiyama, Toshio (2013) DNA looping-dependent targeting of a chromatin remodeling factor. Cell Cycle 12:1809-10
Rodriguez, Jairo; Tsukiyama, Toshio (2013) ATR-like kinase Mec1 facilitates both chromatin accessibility at DNA replication forks and replication fork progression during replication stress. Genes Dev 27:74-86
Au, Tracey J; Rodriguez, Jairo; Vincent, Jack A et al. (2011) ATP-dependent chromatin remodeling factors tune S phase checkpoint activity. Mol Cell Biol 31:4454-63
Yadon, Adam N; Tsukiyama, Toshio (2011) SnapShot: Chromatin remodeling: ISWI. Cell 144:453-453.e1
Vincent, Jack A; Kwong, Tracey J; Tsukiyama, Toshio (2008) ATP-dependent chromatin remodeling shapes the DNA replication landscape. Nat Struct Mol Biol 15:477-84
Kim, Yeonjung; McLaughlin, Neil; Lindstrom, Kim et al. (2006) Activation of Saccharomyces cerevisiae HIS3 results in Gcn4p-dependent, SWI/SNF-dependent mobilization of nucleosomes over the entire gene. Mol Cell Biol 26:8607-22
Lindstrom, Kimberly C; Vary Jr, Jay C; Parthun, Mark R et al. (2006) Isw1 functions in parallel with the NuA4 and Swr1 complexes in stress-induced gene repression. Mol Cell Biol 26:6117-29

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