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.
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.
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