A Weakness in a DNA Repair Mechanism

Corrie Morris

ChemBio Spotlight #7

Paper: Nucleotide Excision Repair is Impaired by Binding of Transcription Factors to DNA. http://www.nature.com/nature/journal/v532/n7598/full/nature17661.html

Somatic mutations in DNA have a variety of causes including exposure to mutagens, such as ultraviolet (UV) radiation, or errors in DNA replication. These mutations can give rise to diseases such as cancer, so it is important that the cell is able to identify and repair this damaged DNA. Nucleotide excision repair (NER) is one such DNA repair mechanism. NER plays an important role in repairing DNA damage caused by UV radiation. Mutations caused by UV radiation are a cause of melanomas (skin cancer). The authors were interested in studying areas of DNA where higher rates of mutation occur.

Variation of mutation rates and NER activity
Variation of mutation rates and NER activity

In the cell, DNA is wrapped around proteins called histones to form nucleosomes (see above image). The authors hypothesized that the bound or unbound state of the DNA might play a role in the frequency of mutations on particular sections of DNA. There was a link between transcription factor binding sites (TFBS) and areas that had more frequent mutations. This led the authors to believe that the binding of these transcription factors to DNA was preventing the NER mechanism from accessing these stretches of DNA.

The authors first analyzed the genomes of multiple melanomas to determine the amount of mutations at TFBS. They discovered that the rate of mutation was significantly higher in DNA regions where transcription factors were actively binding. Active TFBS occur at DNase I hypersensitive sites (DHS) where the DNA is not bound as a nucleosome. It had previously been accepted that NER was more effective at these DHS sites due to the accessibility of the DNA, an idea brought into question by this paper. The combination of unbound DNA and the active binding of transcription factors to that DNA was correlated to a significantly higher mutation rates. This result was replicated across the genome of both cancerous and healthy cells.

The authors then verified that these areas of increased mutation only occur in DHS where transcription factors are binding, not in DHS where nothing is bound to the DNA. This supported the idea that DNA-bound proteins are preventing the components of NER from accessing and repairing mutated DNA. To test this further, the authors induced mutations. XR-seq was used to cut out the mutated regions which were then examined. There was a definite decrease in repair in the TFBS. The results of this paper strongly support the idea that the binding of transcription factors is a hindrance to NER. The unrepaired mutations have been linked to melanomas and certain types of tobacco-related lung cancer.

7 Replies to “A Weakness in a DNA Repair Mechanism”

  1. Interesting article. The review was really great at explaining the basics of NER. From my understanding appears that the mutations unable to be accessed for NER are specifically occurring in the transcription factor binding domain. However, isn’t the transcription binding domain sequence specific for specific transcription factors. So, if mutations are present the transcription factor would potentially not be able to bind allowing for NER to occur. How would you explain this?

  2. Really cool article Corrie. I think it goes along nicely with our theme of acetylation and methylation in epigenetics in our course. You mention that DHS is a site where no nucleosome is binding, but the binding of transcription factors here actually causes for a higher frequency of mutation. Do the authors have an explanation for whether the absence of the nucleosome contributes to this and not just the presence of transcription factors alone? Did they do an experiment to explore how nucleosomes play role and not just the transcription factors?

  3. Very interesting article. I am very curious about the fact that the binding of transcription factors at the DHS was correlated with mutation, but the absence of the binding to DNA translated to no mutations. This confused me because I always that that the binding of transcription factors was done in an attempt to prevent mutations during transcription. The fact that the transcription factors prevented other things from binding at the specific site was very interesting because I would think that normally the factors would work together with other molecules to prevent misreading. Have you come across any other research that suggests other mechanisms other than NER are affected by this competition at the binding site with transcription factors? I am curious if this is very common or if NER is a big exception.

  4. Great article. I thought it was interesting that sites of active transcription factor binding experienced less mutation repair, this likely reduces production of necessary proteins for the conditions that call for such transcription factors, perhaps contributing to development of cancer. The main argument of the article was that the binding of transcription factors prevents NER from fixing the mutations, but i was wondering if the binding of transcription factors or the areas within nucleosomes alter the rate of mutation?

  5. Awesome paper, it’s amazing how much data went into this study! The authors indicate that the frequency of mutations correlates with the strength of the transcription factors’ binding, so couldn’t all DNA-binding proteins induce this effect by sterically blocking the NER mechanism? This paper could carry some serious implications for evolutionary mechanisms considering that the rate of mutation can be as high as 5 times that of actively NER-able regions of DNA.

  6. Really cool article Corrie! It really got me thinking about the frequency with which this occurs, and if there are ways to prevent the transcription factor from actively binding to the DNA when it is not bound in the nucleosome form in cancer patients where this mutation can run wild. Did you come across anything in your research that indicated whether or not DNA binding affinity to histones could be increased as a possible form of prevention, or even treatment? Was there any indication that therapies could be developed in order to prevent or reverse this problem?

  7. Very interesting article, Corrie! I found the authors approach to investigate these DHS for frequency of mutation and relating this phenomenon to NER to be incredibly insightful because it introduces this new concept that these transcription factors negatively impacts NER. I wonder how the medical community would utilize these results in the cases for lung cancer and melanoma. Do the authors discuss potential medical innovations and medicinal research to treat these conditions?

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