The broad, long term goal of the proposed study is to determine, at the molecular level, mechanisms by which chromatin structure is regulated for proper cell cycle control. Chromatin regulation plays integral roles in a wide variety of DNA-dependent processes, including transcription, DNA replication, DNA repair, recombination, kinetochore formation, and DNA damage checkpoint response. Therefore, elucidating the mechanisms of chromatin regulation is a necessary prerequisite for understanding how these essential processes are controlled. One of the major challenges in studying chromatin regulation is to elucidate how chromatin regulation affects such a wide variety of processes in the context of important biological contexts, such as cell cycle control and cell differentiation. This is a particularly important challenge, because it was recently determined that mutations in chromatin regulators represent one major class of so called cancer driver mutations, and how these mutations accerelate cancer development remains unknown. Therefore, elucidating the mechanisms of chromatin regulation impacts not only the researchers who study fundamental principle of DNA-dependent processes, but also those who investigate cancer biology and mechanisms of genome stability maintenance. Our lab has been interested in understanding how chromatin regulation contributes to proper cell cycle progression. We have recently started investigating molecular mechanisms underlying cell quiescence. Proper control of quiescence is essential for the maintenance of stem cell population and prevention of cancer. However, molecular mechanisms that control the entry and maintenance of quiescent cell state have been largely unknown. It was recently found that the budding yeast S. cerevisiae can enter quiescent state that share many properties with mammalian quiescence, and a method to purify the quiescent cell was developed. Taking advantage of this system, we have found that two highly conserved chromatin regulators play central roles in the entry into quiescence. We have also found that DNA replication in the first S phase after yeast cells are released from quiescence is very different from replication in mitotic cell cycle, and shares an important aspect with mammalian DNA replication. Furthermore, we have evidence that proper chromatin regulation plays especially important roles in the initiation of the first DNA replication. Finally, we have obtained evidence that chromatin regulation plays a critical role in determining the timing of replication origin usage during the mitotic cell cycle. We will take advantage of these recent findings and determine how chromatin regulation contributes to proper cell cycle control.

Public Health Relevance

It has been shown that chromatin regulation affects many processes, such as transcription and DNA replication. However, how chromatin regulation affects so many processes in the context of cell cycle control has been a big question in the field. We will address this important question using multiple cutting edge approaches.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Carter, Anthony D
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Fred Hutchinson Cancer Research Center
United States
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Swygert, Sarah G; Kim, Seungsoo; Wu, Xiaoying et al. (2018) Condensin-Dependent Chromatin Compaction Represses Transcription Globally during Quiescence. Mol Cell :
Rodriguez, Jairo; Lee, Laura; Lynch, Bryony et al. (2017) Nucleosome occupancy as a novel chromatin parameter for replication origin functions. Genome Res 27:269-277
McKnight, Jeffrey N; Breeden, Linda L; Tsukiyama, Toshio (2015) A molecular off switch for transcriptional quiescence. Cell Cycle 14:3667-8
McKnight, Jeffrey N; Boerma, Joseph W; Breeden, Linda L et al. (2015) Global Promoter Targeting of a Conserved Lysine Deacetylase for Transcriptional Shutoff during Quiescence Entry. Mol Cell 59:732-43
McKnight, Jeffrey N; Tsukiyama, Toshio (2015) The conserved HDAC Rpd3 drives transcriptional quiescence in S. cerevisiae. Genom Data 6:245-8