Mechanisms and functions of ATP-dependent chromatin remodeling

描述（由申请方提供）：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，其利用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。染色质重塑因子的生理作用的重要性突出的事实是，它们中的许多在各种人类疾病，包括癌症中突变。因此，阐明染色质重塑因子的作用机制和功能，不仅对基础科学，而且对医学都具有重要意义。在当前 在该基金的资助周期中，我们取得了令人惊讶的发现，染色质重塑因子调节非编码RNA（ncRNA）的转录和S期检查点的活性。最近已经清楚的是，真核生物基因组的很大一部分被转录以产生ncRNA。它们中的一些在控制细胞分化中起关键作用， 基因表达和癌症发展。然而，绝大多数ncRNA的生理作用尚不清楚。此外，调节ncRNA转录的机制几乎完全未知。S期检查点在维持基因组稳定性中起着重要作用。然而，它的活动是如何调节的还不清楚。我们将利用 我们最近的研究发现，高度保守的染色质重塑因子调节ncRNA和S期检查点的活动，并阐明这些调节机制的潜在机制和生物学功能。

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.