The broad, long-term goals of the proposed studies are to determine how chromatin structure affects nuclear processes, and how chromatin structure is regulated to accommodate these processes. These are fundamental questions because chromatin regulation affects virtually every biological process that take place in nucleus, including transcription, recombination, DNA repair and DNA replication. Consistent with their importance in understanding chromatin regulation, mutations in numerous chromatin regulators have been linked to human diseases, including cancer. Therefore, studying chromatin regulation will contribute not only to further identification of mechanisms governing basic biological processes, but also to understanding the molecular basis for human diseases. In our previous work, we found that a chromatin regulator Isw2 plays critical roles in both suppression of non-coding transcription and facilitation of DNA replication in our model system, budding yeast Saccharomyces cerevisiae. To elucidate mechanisms and functions of this intriguing chromatin regulator further, we will take multidisciplinary, complementary approaches. We will test our hypothesis that a major role of Isw2 is to be targeted to the ends of genes via a previously unidentified mechanism to protect the genome from abnormal non-coding transcription. In a parallel effort, we will investigate how this complex facilitates DNA replication using molecular genetic approaches. It has become clear that mutations in the human genome that cause abnormal chromatin regulation cause numerous human diseases, including cancer. Our proposed studies elucidate how major regulators of chromatin structure function in cells, contributing to a better understanding of the molecular basis for human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058465-12
Application #
7847416
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
1999-02-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
12
Fiscal Year
2010
Total Cost
$494,350
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Alcid, Eric A; Tsukiyama, Toshio (2016) Systematic approaches to identify functional lncRNAs. Curr Opin Genet Dev 37:46-50
Alcid, Eric A; Tsukiyama, Toshio (2016) Expansion of antisense lncRNA transcriptomes in budding yeast species since the loss of RNAi. Nat Struct Mol Biol 23:450-5
McKnight, Jeffrey N; Tsukiyama, Toshio; Bowman, Gregory D (2016) Sequence-targeted nucleosome sliding in vivo by a hybrid Chd1 chromatin remodeler. Genome Res 26:693-704
Lee, Laura; Rodriguez, Jairo; Tsukiyama, Toshio (2015) Chromatin remodeling factors Isw2 and Ino80 regulate checkpoint activity and chromatin structure in S phase. Genetics 199:1077-91
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 108:21.28.1-16
Alcid, Eric A; Tsukiyama, Toshio (2014) ATP-dependent chromatin remodeling shapes the long noncoding RNA landscape. Genes Dev 28:2348-60
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
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
Yadon, Adam N; Tsukiyama, Toshio (2011) SnapShot: Chromatin remodeling: ISWI. Cell 144:453-453.e1

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