Epi(c)genetics- The Nucleotide excision repair pathway

A fast paced seminar talk presented by Professor Simon Reed, from the institute of genetics and cancer at Cardiff University, was both fascinating and somewhat mindboggling. He and his colleagues have recently focused on the ‘Nucleotide excision repair pathway’ of DNA double stranded breaks, looking specifically at the global genome pathway of repair, involving a protein complex of ABF1, RAD7 and RAD16.

 
Epigenetics:
For all of this to make sense, a quick look at the bigger picture is necessary…which comes in the form of Epigenetics. Epigenetics literally translates as ‘above genetic’ level, meaning that the way that Deoxyribonucleic acid (DNA) is structured and packaged can directly affect the way that genes are translated and expressed in Humans. This packaging is the DNA wrapped around nucleosome and packaged into a structure known as chromosome; at a basic level this looks like beads on a string (figure 1). Alteration by chemicals attaching to the nucleosomes can alter the packaging structure, which could for example make the DNA more or less accessible to promoters, meaning it may or may not be expressed.

 
So how does all of this relate to the previously mentioned protein complex?
One example of this is the role of Rad 16, which is a member of the SWI/SNF super family of chromatin remodelling complexes, which use ATPase motifs to twist DNA, moving the setting of the DNA on the nucleosomes, therefore remodelling the chromatin. A similar process occurs with super helical torsion, which is implemented by DNA translocase activity.

 
Experimentation to confirm the role of the NER genome pathway protein complex:

Here is a short video explaining the process of nucleotide excision repair:

ABF1:
ABF1’s ability to bind to cognate recognition sequences is important in all of its functions in the cell. If a binding defect occurs, due to a mutation for example, then there is a slower removal of lesions from the genome, demonstrating impaired DNA repair in the presence of ultra violet (UV) light. This demonstrates that it has an integral role in DNA repair that is required as a result of UV exposure.

 
RAD16 and RAD7:
Although ABF1 shows very little binding change when exposed to UV, the same cannot be said for RAD16 and RAD7, which exhibits a substantial loss of binding when exposed to UV. This is so that RAD 16 and RAD7 move away from the GG-NER binding site, allowing histone acetyl transferase (HAT) to acetylate the H3 histone, allowing for the global genome Nucleotide excision repair pathway to take place. This may be due to the acetylation causing the DNA to be open to promoters, which may be responsible for DNA repair.

 
This in-depth research is not only very impressive in its finding, it’s also very important. The field of epigenetics has exploded in recent years, and gaining a comprehensive understanding of these mechanisms could be vital in understanding future illnesses, and tailoring treatment specifically to patients. It is hard to grasp that the environment in which we live can directly alter our genetics and their expression, and that this change can be passed on to future generations, so here’s a few news articles for a taste of the more astonishing epigenetic discoveries in recent years:

 
How fear is epigenetically inherited in mice: http://www.bbc.co.uk/news/health-25156510
How stress experienced by pregnant women during the 9/11 attacks in the U.S.A epigenetically affected their children’s stress levels: http://www.theguardian.com/science/neurophilosophy/2011/sep/09/pregnant-911-survivors-transmitted-trauma
Assessing the risk of cancer at an individual level using epigenetics: http://news.bbc.co.uk/today/hi/today/newsid_9717000/9717620.stm

 

Here are some papers by Professor Simon Reed and his collegues, for further reading on the topic:
‘How Chromatin Is Remodelled during DNA Repair of UV-Induced DNA Damage in Saccharomyces cerevisiae’:
http://www.plosgenetics.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1002124&representation=PDF
‘Histone variant Htz1 promotes histone H3 acetylation to enhance nucleotide excision repair in Htz1 nucleosomes’:
http://nar.oxfordjournals.org/content/41/19/9006.full