CANCER AND TUMOUR SUPPRESSOR
The interaction of p53 with DNA requires four molecules – a tetramer. A mutation in one allele that affects the function of the encoded protein could, therefore, produce a p53 tetramer containing mutant and normal (from the unaffected allele) forms that might behave abnormally. When this occurs it can exert ‘dominant’ effects more severe than the loss of an allele. Thus, although P53 is considered to be a member of the tumour suppressor family, it is more complex than RB1. Such complications are not confined to p53: several tumour suppressors can acquire mutations in one allele that change the function of the protein, resulting in a phenotype even with one normal allele. So it isn’t as simple as just knocking out both copies of the gene. For p53 the situation is further complicated by the fact that the gene contains an alternative promoter and can generate multiple splice variants with tissue-dependent expression– these are differentially expressed in tumours compared with normal tissue. Some of the variant forms of p53 produced by alternative splicing actually behave like oncoproteins rather than tumour suppressors – they actively promote abnormal proliferation.
One way in which mutant p53 can modulate cell phenotype is by interacting with a close relative, p63, which is also a transcription factor. This can mis-target p63 to a set of genes that promote invasion. P53 is thus remarkable in that, although the wild-type gene is a potent tumour suppressor, mutations (of just a single amino acid) can generate proteins that are selected for an increasingly invasive and metastatic potential.
The role of p53 is central to the capacity of the cell to repair almost all of the thousands of chemical hits that DNA receives every day from radiation, carcinogens, metabolic by-products and various other assaults. The fact that mutations, caused by many different agents, are repaired so effectively that fewer than one per day remains fixed in the genome suggests that a number of processes are involved. In fact, several hundred genes are devoted to various aspects of DNA repair and these too represent an important class of tumour suppressor. Mutations that impair their function will permit the replication of potential cancer cells and, for obvious reasons, mutations in these genes are said to cause genetic instability.
The autosomal recessive disease xeroderma pigmentosum arises from a genetic defect in the system for repairing DNA damaged by UV light. Sufferers are prone to skin cancers and need to avoid sunlight. Their problem is not with p53, however, which is activated and stops cells from dividing. The time bought is of limited use, however, because DNA repair is defective, the fault most commonly being in the nucleotide excision repair system. In addition to xeroderma pigmentosum, a number of conditions that predispose individuals to cancer are due to DNA repair defects including Werner syndrome, Bloom’s syndrome and Fanconi anaemia. Each occurs because of mutations in proteins that signal or enact the repair process. Ataxia telangiectasia, a rare, inherited neurodegenerative disease that carries an increased risk of cancers, particularly leukaemia and lymphoma, is also often included in this category. It arises from mutations in the ATM protein, a kinase that detects double-strand breaks in DNA and then activates p53: ATM is the reason why p53 is so sensitive to DNA damage. The BRCA2 gene, mutations in which confer a high risk of breast cancer and also a risk of ovarian cancer, encodes a protein that has a role in DNA repair and hence an inherited BRCA2 defect will contribute to genetic instability.