Mutation Frequency Decline

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Mutation Frequency Decline (mfd) is the gene which encodes the protein Mfd (also known as Transcription Repair Coupling Factor, TRCF). Mfd functions in transcription-coupled repair to remove a stalled RNA polymerase that has encountered DNA damage and is unable to continue translocating.

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The protein is named after the fact that it reduces the chances of suppressor mutations in UV-irradiated cells (or rather, knockout cells show higher rates of such mutations). It does not reduce the chance of every kind of mutation. [1] In fact, it seems to increase the chances of mutation in general, helping to evolve new traits such as antimicrobial resistance. [2]

Molecular function

Mfd utilizes ATP to translocate along DNA, most likely forcing RNA polymerase forward and ultimately dissociating it from the DNA template. [3] Mfd also contains binding domains which recruit UvrA and trigger the associated nucleotide excision repair pathway and was initially discovered when its mutation led to a decrease in mutation rates after irradiation by UV light. Structural studies of E. coli Mfd by X-ray crystallography have revealed that this molecule is autoinhibited for UvrA-binding in its apo form due to a "clamp" interaction between the N-terminal UvrB-homology module and the C-terminal domain. [4] [5]

In 2002, it was shown that Mfd may also re-initiate transcription at backtracked RNAP by forcing the polymerase forward and out of its backtracked state. [6]

Cellular consequence

Evolution of antibiotic resistance

In 2015, Merrikh Lab at University of Washington discovered that Mfd quickens the bacterial mutation process. [2] This work researches ways to slow the rate of bacterial mutations and to block their evolution, in order to fight against antibiotic resistance. [7]

In 2022, a small molecule inhibitor of Mfd was identified by the Merrikh lab. As expected, it slowed down the evolution of antibiotic resistance. [8]

Tolerance of nitrogen monoxide

Animal immune systems try to kill bacteria in a number of ways, one being the release of nitrogen monoxide (NO). NO damages bacterial DNA, but some species can survive this attack by expressing Mfd. [9]

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References

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