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Monitoring mutation dynamics in real-time

A central goal in genetics is to understand how mutation rates are regulated by the many genes that act in the creation or prevention of mutations. This fundamental questions remains despite decades of research, mostly because the methods to measure mutagenesis rely on accumulating mutations over time in large populations of cells.

DNA mismatches are detected as fluorescent foci inside living E. coli cells growing inside microfluidic channels. Treatment of cells with DNA damage increases the frequency of DNA mismatches

DNA mismatches are detected as fluorescent foci inside living E. coli cells growing inside microfluidic channels. Treatment of cells with DNA damage increases the frequency of DNA mismatches
(Click to Enlarge)

A new study by Stephan Uphoff published in the journal PNAS utilised a method to monitor mutagenesis in real-time in individual cells. With microscopy, it was possible to detect nascent DNA mismatches - the precursors of mutations - as fluorescent spots within growing and dividing cells. For the first time, the study revealed real-time changes in mutation rates after exposure to DNA damage. Surprisingly, mutagenesis occurred in a distinct pulse that was shaped by the expression of alternative genome maintenance pathways.

The discovery addresses the long-standing question what determines the choice between repair or tolerance of DNA damage, and how this choice affects mutagenesis. The results show that the alternative pathways follow a distinct chronology, where mutagenic damage tolerance is required for initial cell survival before the balance shifts in favour of accurate repair pathways. Furthermore, cell-to-cell heterogeneity in gene expression was found to modulate mutation rates.

In addition to the important implications of this work on bacterial genome maintenance, this article also reveals the dynamics of mutagenesis in response to antibiotic treatment.

This work was funded by the Wellcome Trust and a Wellcome-Beit Prize.

Reference:

  1. Uphoff, S. (2018). Real-time dynamics of mutagenesis reveal the chronology of DNA repair and damage tolerance responses in single cells. PNAS 201801101

 

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