RNA polymerase between lesion bypass and DNA repair

Abstract

DNA damage leads to heritable changes in the genome via DNA replication. However, as the DNA helix is the site of numerous other transactions, notably transcription, DNA damage can have diverse repercussions on cellular physiology. In particular, DNA lesions have distinct effects on the passage of transcribing RNA polymerases, from easy bypass to almost complete block of transcription elongation. The fate of the RNA polymerase positioned at a lesion is largely determined by whether the lesion is structurally subtle and can be accommodated and eventually bypassed, or bulky, structurally distorting and requiring remodeling/complete dissociation of the transcription elongation complex, excision, and repair. Here we review cellular responses to DNA damage that involve RNA polymerases with a focus on bacterial transcription-coupled nucleotide excision repair and lesion bypass via transcriptional mutagenesis. Emphasis is placed on the explosion of new structural information on RNA polymerases and relevant DNA repair factors and the mechanistic models derived from it.

A novel skew analysis reveals substitution asymmetries linked to genetic code GC-biases and PolIII a-subunit isoforms

“…TCR specifically targets lesions on the transcribed strand, 68 enhancing the bias of TAM, such as C→T transitions, towards the coding strand. 26 , 69 , 70 Skew analysis captures this strand-bias, with the distribution of S Trs A-T (TCR + ) being shifted to the left of S Trs A-T (TCR − ) distribution, in accordance with an excess of C→T over G→A substitutions on the coding strand. However, there is no correlation of S Trs G-C with TCR ( P - value = 0.239), indicating that this strand-bias does not originate solely from C→T asymmetries, in line with 21 .…”

Stationary-Phase Mutagenesis in Stressed Bacillus subtilis Cells Operates by Mfd-Dependent Mutagenic Pathways

“…Subsequent studies showed that Mfd is a key component of transcription-coupled repair (TCR), which directs the nucleotide excision repair (NER) system to UV-lesions occupying the template strand in transcribed regions [ 9 ]. In E. coli , genetics and biochemical evidence indicates that Mfd mediates high-fidelity repair of DNA lesions or removal of obstacles that block the progress of the RNA polymerase (RNAP) during active transcription [ 10 , 11 , 12 , 13 , 14 ]. At stalled or blocked RNAP-DNA complexes, Mfd first binds RNAP, then dissociates the transcription elongation complex and finally recruits proteins of the NER system.…”

From Mfd to TRCF and Back Again—A Perspective on Bacterial Transcription‐coupled Nucleotide Excision Repair

“…Finally, a third scenario would be that the polymerase could be forced to translocate past the lesion, possibly resulting in misincorporation during RNA synthesis. This process has been described as transcriptional mutagenesis and has been addressed elsewhere .…”