微小染色体维持蛋白在NF-κB转录活性调节中的作用及分子机制

微小染色体维持蛋白（minichromosome maintenance，MCMs）是真核生物中普遍存在的DNA复制解旋酶，在精确的DNA复制调控中发挥关键性作用。染色质上装载大量的MCMs，并分布在远离复制起点的位置，但是其生物学功能还不清楚。在前期工作中，我们发现MCMs与NF-κB相互作用，敲低MCMs显著性地降低NF-κB靶基因的诱导转录。这些结果初步验证了我们提出的“MCMs是重要的NF-κB调节蛋白”的研究假设。本项目将采取分子生物学及细胞生物学等方法，主要研究以下内容：1）探究MCMs在NF-κB转录活性调节中的作用；2）通过验证科学假说，在基因转录起始、延伸和R-loop形成等方面，阐明MCMs调节NF-κB转录活性的分子机制；3）探讨MCMs和FAM21在NF-κB转录调控中的作用关系。本研究对深入了解MCMs在细胞内功能、NF-κB精细复杂调控网络具有重要的科学意义。

Minichromosome maintenance proteins (MCMs) are ubiquitous DNA replication helicases in eukaryotes, and play a central role in the precise regulation of DNA replication. MCM proteins are loaded in excess onto chromatin and distributed on the locations from the replication origins, but their biological function is not clear yet. Our preliminary results shown that MCMs interact with NF-κB, and knockdown of the MCMs dramatically reduces inducible gene transcription of NF-κB targets. These funding have preliminarily verified our research hypothesis that MCMs are important regulatory proteins of NF-κB. This project will use molecular and cellular biochemical methods to describe several key points as follow. Firstly, explore the roles of MCMs in regulation of the NF-κB transcriptional activity. Secondly, by validating the scientific hypothesis, elucidate the molecular mechanism by which MCMs regulate NF-κB transcriptional activity in terms of gene transcription initiation, extension, and R-loop formation. Finally, study on the relationship between MCMs and FAM21 in regulating NF-κB transcriptional activation. This work is of important scientific significance for giving us deep insights into cellular function of MCMs and fine-tuned regulatory network of NF-κB.