DNA is the building block of life, where DNA overall codes for a protein, which then would carry out its function and contribute in some way to the many pathways of life. In many rare instances, a mutation in the base pairing of DNA would lead to whole proteins changing and therefore can cause many diseases. Xeroderma Pigmentosum (XP) is one such disease which is caused by the mutations in genes that are particularly involved in repairing damaged DNA. XP is a genetic, inherited skin condition which is rare, only affecting one in one million people (in the US and Europe) (Reference, 2017), and generally is identified by its characteristic feature of extreme sensitivity to ultraviolet (UV) rays from sunlight. (Lehmann, McGibbon and Stefanini, 2017) XP has at least eight inherited forms, from group A (XP-A) all the way through to group G (XP-G) along with a variant of type V (XP-V). (Reference, 2017) All of the forms of XP increase skin cancer risk, but some forms are more likely than others to be associated with neurological abnormalities. (Reference, 2017)
Usually the most areas affected are the areas of skin constantly exposed to sunlight such as hands and necks, along with other vulnerable areas such as the delicate eye area. In this specific condition, the genetic mutation means the cells cannot repair damaged DNA and as more irregularities in the DNA form and the DNA is not repaired, eventually the cells die or malfunction and become cancerous. Signs and symptoms of XP appear during infancy when after a few minutes of exposure to sunlight, the affected person develops severe sunburn usually a full red and blistering sunburn, whereas others usually are not as affected. Additionally, other symptoms and signs include freckling of exposed skin (which include arms, face and lips) and also dry skin. (Reference, 2017). This shows how important DNA repair mechanisms are in the everyday function of cells, with XP as an example of the mechanism going wrong. Scientists can use the known XP condition to understand more about the underlying processes associated with how DNA damage is repaired.
The primary cause of numerous genetic conditions is DNA damage, which can occur in many ways however certain agents can lead to DNA damage. Many agents that can cause DNA damage include: specific wavelengths of radiation (ionizing radiation such as gamma rays and X-rays, and ultraviolet rays, especially the UV-C rays that are absorbed strongly by DNA), highly-reactive oxygen radicals and many chemicals. (Biology-pages.info, 2017) In the specific case of XP, they are most susceptible to UVB (responsible for sunburn and some skin cancers) and UVA rays (responsible for skin ageing and possibly now thought to contribute to some skin cancers). Overall UV rays cause the most risk to people with XP as when exposed to them, cell damage occurs which the XP patients can’t repair. (Xeroderma pigmentosum: using an Ultraviolet (UV) meter, 2017) Additionally, people with XP have a risk of developing skin cancer and may develop multiple skin cancers throughout their life due to a malfunctioning DNA repair system (Reference, 2017). Skin cancer is a good example of environmental-induced DNA damage as it can be caused by excessive UV exposure. (Clancy, 2017)
Although there are many agents which can lead to mutations, there are also many DNA repair mechanism in place to minimise their effects. Everyday DNA replication gives rise to many mutations, however not all these mutations result in diseases due to repair mechanisms. Although any mutated cell can move onto the apoptotic and senescent stage, that only occurs as a final resort, after DNA repair mechanisms occur. The repair mechanisms include: direct chemical repair and excision repair (base excision repair – BER, nucleotide excision repair – NER and mismatch repair – MMR). (Biology-pages.info, 2017; Cooper, 2017) BER uses many enzymes to remove and replace a single damaged nucleotide base (Sigma-Aldrich, 2017) whereas NER repairs damage to a nucleotide strand which contains at least 2 bases, and create a structural distortion in the DNA. In this instance, we are interested in nucleotide excision repair mechanism (NER) which is a key player for the XP condition. Most of the genes that are related to XP also play vital roles in the NER pathway, which is why people with XP cannot repair DNA which has been damaged by UV light. (Reference, 2017) The proteins recognise DNA damage, unwind those specific regions of DNA and excise the irregular sections along with replacing the damaged areas with the right DNA. By finding out more about specific proteins involved in the NER pathway and chain of events that take place, it allows us to be able to gain a better understanding of the exact process behind DNA damage repair.
XP was the first disease to be identified which relates to nucleotide excision repair (NER) mechanism and can be used as a model to identify the specific genes which are responsible for NER, as well as why the DNA repair mechanisms are essential to prevent mutations. The underlying cause of XP is the defective process of removing the damaged DNA through NER, which can help us understand how DNA damage is repaired by being used as a comparison against an individual without XP. Firstly, due to exposure to UV light, 2 specific classes of lesions occur (cyclobutane pyrimidine dimers – CPDs, and 6-4 photoproducts – 6-4 PPs) which distort the DNA molecules. (Nakajima et al., 2017) NER removes the abnormal DNA lesions (not only UV induced) (Carlos FM Menck, 2017) as the distortions lead to kinks and bends which can stop transcription and replication. There are four steps involved in NER process: damage detection, excision of that section of DNA, filling in gap using DNA polymerase and sealing the opening. (Clancy, 2017) Overall this whole process needs the proteins made from approximately 30 genes, and it is the mutations on these genes which lead to the change of protein and possibly XP. (Clancy, 2017) This shows how similar NER is to the checkpoints involved in the cell cycle as they both are essential for the cell before DNA replication begins. NER is extremely important as before DNA replication begins, it allows the total amount of damage and rate of any errors to be reduced. By knowing XP have UV light induced lesions, we find out more about the specific characteristics of DNA that the NER pathway targets.
The cause of XP is any mutations which would occur in any of the genes involved in the NER pathway. These genes include: XPA (which encodes a protein that binds the damaged site and helps assemble the other proteins needed for NER), XPB and XPD (are part of system which unwinds DNA), XPF (cuts the backbone on the 5′ side of the damaged DNA) and XPG (cuts the backbone on the 3′ side) (Biology-pages.info, 2017) Since XP is caused by a failure in the NER pathway, it can easily show that NER is important in DNA damage repair and also that since XP occurs due to mutations in multiple genes, many proteins are involved in NER along with NER being a multistep pathway with a requirement for many proteins. Although many other factors may play a role in XP, NER is the main contributing factor, meaning there is little to no interference from other processes, allowing is to effectively work out how NER works for someone with XP. Since XP is missing the DNA repair mechanism, it leads to not being able to repair damaged cells, showing that the main repair mechanism would be NER as even though the other excision repair mechanisms can still work, in this specific instance they are not effective in repairing the UV induced damage.
All the body systems seem to work together, for instance DNA damage repair is not solely the responsibility of NER but each repair mechanism has their own specialty and category for repair. BER and MMR are also excision repair mechanisms however are not effective in dealing with a XP condition as they cannot specifically repair DNA which is damaged by UV light. Since NER does not function it leads to XP, however BER works and still cannot repair the DNA, showing that the mutations responsible for XP are not a base large but are of nucleotides which is why only NER functions. NER is not only for the UV light but any helix-distorting lesions, meaning the function is also slightly versatile which is important for any body/cell systems.
In conclusion, XP is highly effective at telling us more about how DNA damage is repaired as it is linked to NER which is one of the mechanisms used to repair damaged DNA. Quite successfully XP shows us how important the DNA repair mechanisms are by acting as a model for what would happen if DNA repair systems were not working well and how complicated the DNA damage repair mechanism thus justifying its need for multiple proteins. The NER mechanism is important to other processes which strongly show how intertwined the whole human body (and cell) systems are.