biologyScience

Protein has a dual role: both repair and mutation

  • The Mfd protein repairs bacterial DNA, but it can also, to scientists’ surprise, boost the mutation.
  • Bacterial mutations can lead to antibiotic resistance.
  • Understanding this second “role” of Mfd opens opportunities to combat antibiotic resistance, as well as resistance to tumors to drugs and anti-cancer therapies.

With a specialized protein, all bacteria are able to quickly and effectively repair damage to DNA from UV rays. However, the Mfd protein plays another role and causes mutations. A team including scientists from CNRS and ENS-PSL, with support from Inserm, has clarified and described this phenomenon. A better understanding of mutations opens the door to fighting antibiotic resistance and anti-cancer treatments. This study was published in PNAS On April 5, 2021.

DNA can undergo many degradations, including UV degradation. Just as a landslide on a railroad track will prevent a train from passing, damage from UV rays is an obstacle to the RNA polymerase, a protein that travels along the length of the DNA to read its instructions. An RNA polymerase that is blocked at any time prevents damage from repairing. To restore the “pathway,” the bacteria possess the Mfd protein that removes the blocked RNA polymerase, and then recruits other proteins to aid in the repairs, avoiding mutations.

Biologists from Institut de Biologie de l’ENS (CNRS / ENS – PSL / INSERM) have just solved the mystery of a lesser known role for this protein. It participates in forming DNA regions where mutations appear more easily.

The cell machinery that comprises the Mfd protein usually repairs the DNA, but when the bacteria encounters certain stresses, such as the presence of an antibiotic, they take another route: Mfd clings to the active RNA polymerase as it passes through the DNA, rather than clearing a clogged component. RNA polymerase. Once the two proteins are bound together, the two proteins disassemble the DNA double helix quickly and extensively, forcing it to open. The opening of the two DNA strands creates a favorable environment for the formation of specific regions that facilitate mutations: R loops.

R-rings are still not well understood, but they are the source of many mutations: Scientists have shown that nearly half of the mutations in bacteria are due to these structures. Because antibiotic resistance arises from mutations, this work, which elucidates the link between Mfd and R loops, opens new avenues in the fight against antibiotic resistance.

The research team also indicates that Mfd has equivalents in various branches of life and that this mutation mechanism may be universally present. In humans, for example, the protein corresponding to Mfd is involved in accelerating aging and the development of tumor resistance to chemotherapy. Scientists believe that a similar mechanism for R-ring formation could occur in cancer cells, leading to mutations that could make them resistant to treatment.

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