6 – The Guardian of the Genome

For the series of entries so far, I realise I have concentrated on fully developed cancers or their causes. But this leaves an important aspect of the field uncovered, what stops the potential tumour cells that don’t become fully fledged cancers? Today’s entry is about the body’s defences, focusing on the protein P53, also known as the Guardian of the Genome.

But what is p53? To put it simply, it controls what genes your body is making use of, almost like a teacher instructing a student on what to read to benefit them most. It kicks in when the cell detects DNA damage (which you’ll remember is what causes cancer-generating mutations), and activates a host of responses to try and prevent that damage resulting in mutations. P53 itself is made up of 4 identical but separate proteins joined as one. This type of structure is called a homotetramer.

p53, the homotetramer shield protecting the DNA of almost every cell.

It responds to quite a few cancer indicators, which include:

• UV radiation, the reason sunlight causes skin cancer.
• Ionising radiation, such as X-rays and the gamma rays given off by certain radioactive material.
• Hypoxia, a lack of oxygen, which if you think back to the hallmarks could indicate cancer as cells in the centre of a tumour have little oxygen until a blood supply is established.
• A lack of nucleotides, which are the building blocks that make up DNA, a rapidly dividing cancer cell must also copy its DNA very quickly, which eventually causes supplies of this chemical to dwindle.

P53 responds to these events with the help of a molecule called MDM-2, which ironically, stops p53 working. While this sounds counter-intuitive, it is in fact part of a clever ‘reverse switch’. If one of the trigger events above occurs, this MDM-2 protein is inactivated, allowing p53 to do its job.

MDM-2 binds to each of the four p53 subunits, inactivating it, but separates when any of the DNA damage signals are detected.

To prevent the uncontrolled growth exhibited by cancer cells, p53 causes a number of molecules involved in growth arrest to be produced. An example is p21, which stop growth by interfering with many systems.

P53 also activates the process of apoptosis, which is where (rather nobly) the cell kills itself because of irreparable damage. This is a complicated process which would require another post to explain in full, but essentially three processes are involved. P53 causes the production of: a molecule called Bax that causes the cell mitochondria to release lethal substances, a molecule called IGFBP-3 that blocks signals that keep the cell alive, and a molecule called Fas that sits on the surface of the cell and relays signals for the cell to kill itself from elsewhere in the body.

The three major ways p53 causes apoptosis. The intrinsic pathway (Bax), the extrinsic pathway (Fas) and by blocking cell survival signals.

P53 also targets the sustained angiogenesis hallmark, causing more of molecules such as thrombospondin-1 to be produced, this blocks the signals required to attract blood vessels to the cell, depriving it of much needed oxygen.

As well as interfering with several hallmarks, p53 increases the amount of proteins involved in DNA repair present in the cell. An example would be the XPC, XPE AND XPG proteins involved in the process of nucleotide excision repair (or NER). This is the system by which the body repairs the damage caused to DNA by UV light (so sunbed users, be grateful p53 is watching over each of your cells!). ⁽¹⁰⁾

As a result of its many functions, any mutation causing the loss of p53 function can be catastrophic for a cell. Indeed, studies with mice show that a lack of p53 function leads to a lifespan of only 4.5 months compared to a normal mouse’s 27-month lifespan. Studies with mice have also shown that those with no p53 activity also show much reduced apoptosis, ⁽¹²⁾ which highlights just how important this protein is for certain cancer defences. In humans, a mutation in p53 is most prevalent in ovarian, oesophagus (food tube in neck) and colorectal cancers. In ovarian cancers almost 50% display this mutation. It is least common in cancers of the testis, thyroid gland and uterus/cervix. Appearing in only 5% of cases of the latter.

Many of these mutations make it more difficult for the four parts of the p53 tetramer to stay together, causing it to be broken down and stop functioning.  Many therapies for this type of mutation stop the mutated p53 from coming apart, an example of this is the PRIMA-1 treatment, that has restored the activity of p53 in cells displaying this type of mutation.

Cancer is an awfully scary disease, but that doesn’t mean you should live your life in fear of it, defence mechanisms such as p53 work tirelessly to prevent the development of Cancer and most of the time, they are very good at their job.