Nucleotide excision repair is universally mutagenic and transcription-associated

Nucleotide excision repair (NER) is a highly conserved mechanism that removes lesions from DNA. This process has been studied for decades, however, almost all of the work on NER was performed in the presence of exogenous DNA damage. Under these conditions, NER is anti-mutagenic in bacteria. Here, we describe our findings on the role of NER in mutagenesis under endogenous conditions. Counter to dogma, we find that NER is actually pro-mutagenic. Our data suggest a hand-off mechanism between two different types of DNA polymerases that explains the mutagenic nature of NER. Additionally, NER is thought to occur in two different ways; 1) in a transcription-coupled manner where it plays a role in removing lesions that block RNA polymerase, and 2) in a process known as global genome NER, which is independent of transcription. Counter to the classical view, our genetic analyses of the relationship between NER and the RNA polymerase interacting DNA translocase, and evolvability factor, Mfd, indicate that most likely all NER is associated with transcription. Lastly, we show that NER is pro-mutagenic because of endogenous oxidative damage. Altogether, our data strongly suggest that oxidative damage induces a mutagenic NER mechanism, which then accelerates evolution across divergent bacterial species. ### Competing Interest Statement The authors have declared no competing interest.