2011 Publication

Abstract:

The RNA Pol II transcription complex pauses just downstream of the promoter, in a significant fraction of human genes. The local features of genomic structure that contribute to pausing have not been defined. Identification of those features has important implications for understanding both mechanisms of genomic instability and the response of cells to drugs that affect pausing, such as the topoisomerase I poison, camptothecin. We have previously shown that almost half of human protein coding genes contain regions bearing a G4 motif at the 5' end of the first intron, on the nontemplate DNA strand, referred to as G-rich intron 1 elements (GrIn1 elements). Regions bearing GrIn1 elements have the potential to form G-loops upon transcription, which contain co-transcriptional RNA/DNA hybrids in the template strand and G4 DNA interspersed with single-stranded regions on the non-template strand. Here we show that genes that pause are more G-rich in the region flanking the TSS than RefSeq genes or non-paused genes. We further show that pausing correlates with the presence of a GrIn1 element, and the potential for formation of G-loops during transcription. These results suggest that GrIn1 elements may function as dynamic structural elements that regulate pausing in cis, thereby contributing to genome-wide regulation of gene expression. These elements may also influence local vulnerability to AID, a DNA deaminase that promotes genomic instability, and to cellular sensitivity to agents that perturb the normal dynamics of DNA structure formation during transcription.