转录与前 mRNA 代谢的耦合-猫眼课题宝

转录与前 mRNA 代谢的耦合

批准号：

8600691

负责人：

DAVID L BENTLEY

金额：

$37.2万

依托单位：

UNIVERSITY OF COLORADO DENVER

依托单位国家：

美国

项目类别：

财政年份：

1999

资助国家：

美国

项目状态：

已结题

起止时间：

1999-01-01 至 2015-12-31

来源：

https://reporter.nih.gov/project-details/8600691

关键词：

Address Affect Alternative Splicing Biochemical Biogenesis Breast Breast Cancer Cell C-terminal Cancer cell line Cells ChIP-seq Chromatin Chromatin Structure Code Communities Complex Coupling Cytoplasm DNA DNA-Directed RNA Polymerase Defect Event Gene Components Genes Genetic Genetic Transcription Guanine Nucleotide Exchange Factors Histones Length Life Maps Messenger RNA Metabolism Modeling Modification Normal Cell Nuclear Export Nucleosomes Pathway interactions Pattern Phase Phosphorylation Play Poly A Polyadenylation Polymerase Process Production Proteins RNA RNA Binding RNA Caps RNA Polymerase II RNA Processing RNA Splicing RNA chemical synthesis RNA, Messenger, Splicing RNA-Binding Proteins Recruitment Activity Resolution Role Serine Set protein Signal Transduction Site Thinking Time Transcript Transcription Elongation Transcription Process Work cancer cell cell transformation chromatin modification genome-wide analysis histone modification mRNA Precursor messenger ribonucleoprotein protein expression public health relevance

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DESCRIPTION (provided by applicant): Making messenger RNA (mRNA), the primary event in expression of protein coding genes is central to the life of all cells and its corruption is a hallmark of cancer cells. mRNA synthesis requires transcription by RNA polymerase II (pol II) to produce a precursor that is matured by capping, splicing and cleavage/polyadenylation and packaged with RNA binding proteins into mRNP's for export to the cytoplasm. The template that is transcribed is made of chromatin: DNA wrapped around histone proteins in assemblies called nucleosomes. Transcription and pre- mRNA processing are not independent events; they are integrated with one another in a manner that depends on a specialized domain of RNA pol II called the CTD that acts as a landing pad for processing proteins. In fact transcripts made by RNA polymerases other than pol II or those made by pol II lacking the CTD are not processed correctly into mature mRNA. Our working hypothesis is that synthesis and processing of mRNA precursors is performed by an 'mRNA factory' complex which comprises pol II and processing factors held together by contacts with the CTD. This model is an example of a new way of thinking about a set proteins that were once thought to operate independently of one another rather than as a integrated team. We use genetic and biochemical approaches to ask how the 'mRNA factory' works to achieve efficient and accurate production of export-competent mRNP's coordinated synthesis and maturation of transcripts made by pol II. The objectives of this proposal are to 1. To determine the mechanism that permits cross-talk between pre-mRNA splicing and modification of chromatin structure. 2. To map patterns of pol II CTD phosphorylation at high resolution and determine how they related to co-transcriptional assembly of splicing and 3' end processing complexes in normal breast cells and breast cancer cells. 3. To determine how assembly of export competent RNP's is coordinated with processing of the mRNA by cleavage-polyadenylation.

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