RNA Polymerase Collision versus DNA Structural Distortion: Twists and Turns Can Cause Break Failure

Abstract

Summary The twisting of DNA due to the movement of RNA polymerases is the basis of numerous classic experiments in molecular biology. Recent mouse genetic models indicate that chromosomal breakage is common at sites of transcriptional turbulence. Two key studies on this point mapped breakpoints to sites of either convergent or divergent transcription, but arrived at different conclusions as to which is more detrimental and why. The issue turns on whether DNA strand separation is the basis for the chromosomal instability or collision of RNA polymerases?

Lingering Questions about Enhancer RNA and Enhancer Transcription-Coupled Genomic Instability

“…Transcription of the lncRNA is in the opposite orientation to that of the BCL6 gene, leading to the consideration that divergent transcription may be implicated in defining translocation fragile zones. Divergent transcription results in single-stranded DNA, which is necessary for AID action, and it had been shown previously that AID actively deaminates cytidine targets in this particular breakpoint region [38,40,41]. This report in the literature connects divergent transcription, AID activity, lncRNA expression, superenhancer location, and genomic breakpoints.…”

“…The mechanism of such instability is due either to the physical collision of the two RNA polymerases [67,70], and/or to the generation of nucleosome-free single-stranded DNA caused by the negative supercoiling present in the two passing RNA polII complexes, positioned in a divergent configuration during the process of transcription. These mechanistic possibilities are detailed in [40,41]. To this end, it has been shown that some of the bidirectionally transcribed regions of the B cell genome, where genomic instability occurs (including putative intragenic enhancers), have nucleosome depletion and accumulation of single-stranded DNA conformations ([11]).…”

The constrained architecture of mammalian Hox gene clusters

“…The decrease in the steady-state level of Hoxd12 transcripts upon Hoxd11 inversion may reflect a collision effect, with transcripts elongating from Hoxd11 and reaching the Hoxd12 3′ UTR, thus interfering with the correct transcription of this latter gene and its mRNA's stability. In Saccharomyces cerevisiae, the main source of transcriptional interference is caused by the frontal collision between 2 transcriptional machineries moving on opposed DNA strands (32)(33)(34). These collisions result in mutual arrest of the 2 complexes, leading to their dissociation from the DNA through polyubiquitylation of the RNA polymerase II and the degradation of the aborted RNA transcripts (35)(36)(37)(38).…”

Constrained Transcriptional Polarity in the Organization of MammalianHoxGene Clusters

“…The decrease in the steady state level of Hoxd12 transcripts upon Hoxd11 inversion may reflect a collision effect, with transcripts elongating from Hoxd11 and reaching the Hoxd12 3' UTR, thus interfering with the correct transcription of this latter gene and its mRNA's stability. In S. cerevisiae, the main source of transcriptional interference is caused by the frontal collision between two transcriptional machineries moving on opposed DNA strand (Hao et al 2017;Pannunzio and Lieber 2016;Palmer et al 2011). These collisions result in mutual arrest of the two complexes, leading to their dissociation from the DNA through polyubiquitylation of the RNA Pol II and the degradation of the aborted RNA transcripts (Hobson et al 2012;Osato et al 2007;Prescott and Proudfoot 2002;Somesh et al 2005).…”