Debunking myths on genetics and DNA

Monday, March 12, 2012

How nucleosomes "protect" our DNA

Did you know that not all mutations happen at an equal rate? There are several kinds of mutations: substitutions, insertions, deletions, etc. Insertions and deletions happen when bits of DNA are either inserted or deleted, whereas substitutions happen when the overall length of the DNA locus doesn't change, but a base is substituted for another. As you all know, we have 4 nucleotides (A, C, G, and T), however, not all possible changes are equally likely. The most frequent substitutions are As with Gs and Cs with Ts.

Mutations happen because of errors in DNA replications or because of DNA lesions. These are chemical processes that are more or less likely depending on the circumstances. For example, DNA is "stronger" when it's a double helix, although occasionally the bonds between the two helices can locally denature, opening up a chance for a mutation to happen.

In all nucleated cells DNA is packaged inside the nucleus in units called nucleosomes: threads of DNA (~147 base pairs) wrap around "spools" formed by 8 protein units called histones. When the DNA is packed into nucleosomes it is more resistant and less prone to mutations. At the same time, chromatin, the assembly of all nucleosomes inside the nucleus, is hardly ever static. See this post where I discuss how nucleosomes are reassembled in order to promote the expression of certain genes versus others (a phenomenon called "chromatin remodeling"). A new study [1] published in the latest issue of Science investigates how the structure and assembly of DNA inside the cells affects the likelihood of certain mutations versus others. They found that nucleosomes act as regulators for substitution mutations, protecting DNA from damage. For example, compared to other DNA states, nucleosomal DNA undergoes 50% less C -> T mutations.
"Furthermore, the rates of G -> T and A -> T mutations were also about two-fold suppressed by nucleosomes. On the basis of these results, we conclude that nucleosome-dependent mutation spectra affect eukaryotic genome structure and evolution and may have implications for understanding the origin of mutations in cancers and in induced pluripotent stem cells."
Without getting into too many technical details, Chen et al. looked at the initial nucleosome profile from two replicates of the yeast Saccharomyces cerevisiae strain Y55, and then tracked subsequent mutations. They also looked at SNPs (single-nucleotide polymorphisms) in the germline of the Japanese killifish medaka. Germline cells are cells that give rise to oocytes and spermatocytes, hence mutations in this line are of evolutionary importance since they get carried on to subsequent generations.
We have revealed that nucleosomes, the most abundant eukaryotic protein-DNA complexes, likely function as a major regulator of substitution mutations in eukaryotes. Binding of proteins to DNA to suppress DNA breathing or to exclude endogenous mutagens may be how cells protect their DNA. However, DNA repair, which often works with varied efficiency between nucleosomal DNA and naked DNA, may also shape the base-specific mutation spectrum."
Chen, X., Chen, Z., Chen, H., Su, Z., Yang, J., Lin, F., Shi, S., & He, X. (2012). Nucleosomes Suppress Spontaneous Mutations Base-Specifically in Eukaryotes Science, 335 (6073), 1235-1238 DOI: 10.1126/science.1217580

Photo: light reflections (or is it refractions?) on a soap bubble. Shutter speed 1/125, focal length 100mm, F-stop f5, ISO speed 100.


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