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Extreme C-to-A Hypermutation at a Site of Cytosine-N4 Methylation.

ABSTRACT: Methylation of cytosine in DNA at position C5 increases the rate of C→T mutations in bacteria and eukaryotes. Methylation at the N4 position, employed by some restriction-modification systems, is not known to increase the mutation rate. Here, I report that a Salmonella enterica Type III restriction-modification system that includes a cytosine-N4 methyltransferase causes an enormous increase in the rate of mutation of the methylated cytosines, which occur at the overlined C in the motif CACC̅GT Mutations consist mainly of C→A transversions, the rate of which is increased ∼500-fold by the restriction-modification system. The rate of C→T transitions is also increased and somewhat exceeds that at C5-methylated cytosines in Dcm sites. Two other Salmonella N4 methyltransferases investigated do not have such dramatic effects, although in one case there is a modest increase in C→A mutations along with an increase in C→T mutations. The sensitivity of the C→A rate to orientation with respect to both DNA replication and transcription is higher at hypermutable sites than at other cytosines, suggesting a fundamental mechanistic difference between hypermutation and ordinary mutation.IMPORTANCE Mutation produces the raw material for adaptive evolution but also imposes a burden because most mutations are deleterious. The rate of mutation at a particular site is affected by a variety of factors. In both prokaryotes and eukaryotes, methylation of C at the C5 position, a naturally occurring DNA modification, greatly increases the rate of C→T mutation. A distinct C modification that occurs in prokaryotes, methylation at N4, is not known to increase mutation rate. Here, I report that a bacterial restriction-modification system, found in some Salmonella bacteria, increases the rate of C→A mutation by a factor of 500 at sites that it methylates at N4. This rate increase is much greater than that caused by C5 methylation. Although fewer than 1 in 1,600 positions analyzed are methylation sites, over 10% of all mutations occur at these sites. Like other examples of extremely high mutation rate, whether naturally occurring or the result of laboratory mutation, this phenomenon may shed light on the mechanism of mutation in general.

SUBMITTER: Cherry JL

PROVIDER: S-EPMC8092215 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytosine DNA methylation (CDM) is a stable epigenetic modification to the genome and a widespread regulatory process in living organisms that involves multicomponent molecular machines. Genome-wide cytosine methylation patterning participates in the epigenetic reprogramming of a cell, suggesting that the biological information contained within methylation positions may be amenable to decoding. Adaptation to a new cellular or organismal environment also implies the potential for genome-wide redistribution of CDM changes that will ensure the stability of DNA molecules. This raises the question of whether or not we would be able to sort out the regulatory methylation signals from the CDM background ("noise") induced by thermal fluctuations. Here, we propose a novel statistical and information thermodynamic description of the CDM changes to address the last question. The physical basis of our statistical mechanical model was evaluated in two respects: 1) the adherence to Landauer's principle, according to which molecular machines must dissipate a minimum energy ? = kBT ln2 at each logic operation, where kB is the Boltzmann constant, and T is the absolute temperature and 2) whether or not the binary stretch of methylation marks on the DNA molecule comprise a language of sorts, properly constrained by thermodynamic principles. The study was performed for genome-wide methylation data from 152 ecotypes and 40 trans-generational variations of Arabidopsis thaliana and 93 human tissues. The DNA persistence length, a basic mechanical property altered by CDM, was estimated with values from 39 to 66.9 nm. Classical methylome analysis can be retrieved by applying information thermodynamic modelling, which is able to discriminate signal from noise. Our finding suggests that the CDM signal comprises a language scheme properly constrained by molecular thermodynamic principles, which is part of an epigenomic communication system that obeys the same thermodynamic rules as do current human communication systems.

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Extreme C-to-A Hypermutation at a Site of Cytosine-N4 Methylation.

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