Mechanisms and functions of ATP-dependent chromatin remodeling

描述（由申请人提供）：拟议研究的广泛，长期目标是在分子水平上确定体内atp依赖性染色质重塑的机制和功能。ATP依赖性染色质重塑因子是高度保守的ATP酶，利用ATP水解的能量来改变染色质结构。由于其生物化学活性和高丰度，atp依赖性染色质重塑因子可以影响多种DNA依赖性过程，包括转录、DNA复制和DNA损伤修复。许多染色质重塑因子在包括癌症在内的各种人类疾病中发生突变，这一事实突出了染色质重塑因子所起的生理作用的重要性。因此，阐明染色质重塑因子的机制和功能不仅对基础科学有重要影响，而且对医学也有重要影响。在当前

DESCRIPTION (provided by applicant): 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.