Molecular mechanism and regulatory function of protein coding gene transcriptional termination in mammalian genomes.

The enormous facility with which mammalian genomes can be sequenced has outstripped our understanding of gene function in a genomic context. This disconnect between genomics and gene mechanism is especially evident in understanding how gene transcription units are defined. The major vision behind my proposal is to determine which genes terminate transcription by which mechanism and how this impacts on gene expression. To achieve this we will combine genomic analysis of nascent transcription with mechanistic studies that rely on molecular biological and biochemical analysis. Aims: 1) We will define in molecular detail the common mechanisms that mediate efficient transcriptional termination. 2) We will annotate which termination mechanisms act on which protein coding genes and how this may impact on their expression. 3) Many previously considered ubiquitous termination factors only affect a subset of protein coding genes. We aim to understand why this is the case and how it relates to gene regulation. 4) Transcriptional termination directly interconnects with all other stages of transcription. We will investigate the molecular basis of these interconnections. 5) Loss of termination causes read-through transcription (fused transcripts) a feature ofcancer cells. This suggests that cancer causes breakdown in normal transcription unitdefinition. We aim to better understand why termination is defective in cancer.