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Abstract
The mfd (mutation frequency decline) gene was identified by screening an auxotrophic Escherichia coli strain exposed to UV and held in a minimal medium before plating onto rich or minimal agar plates. It was found that, under these conditions, holding cells in minimal (nongrowth) conditions resulted in mutations that enabled cells to grow on minimal media. Using this observation as a starting point, a mutant was isolated that failed to mutate to auxotrophy under the prescribed conditions, and the gene responsible for this phenomenon (mutation frequency decline) was named mfd. Later work revealed that mfd encoded a translocase that recognizes a stalled RNA polymerase (RNAP) at damage sites and binds to the stalled RNAP, recruits the nucleotide excision repair damage recognition complex UvrA2UvrB to the site, and facilitates damage recognition and repair while dissociating the stalled RNAP from the DNA along with the truncated RNA. Recent single-molecule and genome-wide repair studies have revealed time-resolved features and structural aspects of this transcription-coupled repair (TCR) phenomenon. Interestingly, recent work has shown that in certain bacterial species, mfd also plays roles in recombination, bacterial virulence, and the development of drug resistance.
Highlights
The mfd gene was identified by screening an auxotrophic Escherichia coli strain exposed to UV and held in a minimal medium before plating onto rich or minimal agar plates
Later work revealed that mfd encoded a translocase that recognizes a stalled RNA polymerase (RNAP) at damage sites and binds to the stalled RNAP, recruits the nucleotide excision repair damage recognition complex UvrA2UvrB to the site, and facilitates damage recognition and repair while dissociating the stalled RNAP from the DNA along with the truncated RNA
This was 4 years before the discovery of Escherichia coli RNA polymerase (RNAP; Hurwitz et al, 1960), and several years before it was even known that thymine dimers were the major UV lesions in E. coli DNA (Wacker et al, 1962) and that such dimers are repaired in E. coli either by a visible light–dependent photoreactivating enzyme (Rupert et al, 1958), Abbreviations: Mfd, mutation frequency decline; RNAP, RNA polymerase; NER, nucleotide excision repair; GGR, global genome repair; transcriptioncoupled repair (TCR), transcription-coupled repair; TRCF, transcription-repair coupling factor; CPD, cyclobutane pyrimidine dimer; XR-seq, excision repair-sequencing; ChIP-seq, chromatin immunoprecipitation followed by high-throughput sequencing; RNAP interaction domain (RID), RNA polymerase interaction domain; EM, electron microscopy
Summary
Even though the Mfd protein has been extensively studied for nearly three decades since it was cloned (Selby and Sancar, 1993a) and characterized (Selby and Sancar, 1993b, 1994, 1995a,b) by Selby, several recent reports have significantly advanced our understanding of Mfd, including discoveries from whole-genome analyses (Adebali et al, 2017a,b; Ragheb et al, 2021), as well as from structural (Brugger et al, 2020; Kang et al, 2021) and single-molecule (Fan et al, 2016; Ho et al, 2018, 2020; Ghodke et al, 2020) studies which will be reviewed here.
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