DNA is exposed continuously to damage by agents including ionizing radiation (which causes single or double strand breaks), reactive oxygen species (ROS) (due to a deficiency of antioxidants resulting in attacks at purine and pyrimidine rings) and alkylating agents (such as heterocyclic amines from foods that form DNA adducts), and acquires errors during replication. For a unicellular organism, repair of DNA is the only option if the cell is to survive with normal function. In contrast, metazoans can 'choose' to kill off damaged cells by apoptosis if the cost or risks associated with repair are too great. Apoptosis may be the prudent course of action for damaged stem cells or other cells with substantial proliferative potential but, for post-mitotic cells, or those with a limited life span (gut epithelium or skin), repair may be a 'safe' option (Evan and Littlewood, 1998). The evolutionary origins of apoptosis remain obscure but it has been argued that single-celled organisms could have evolved a cell death programme 'as a contingent strategy to prevent infection of related individuals' (Vaux, 2002).
As a form of defence, cells with DNA damage arrest at the G1-S cell cycle checkpoint when damage is sensed by the protein product of the ATM gene. Inherited mutations in this gene are responsible for the rare recessive disease ataxia telangiectasia, which is characterized by cerebellar ataxia, dilation of the blood vessels of the eye, immunodeficiency and growth retardation, and by a strong predisposition to cancer (Strachan and Read, 1999). By processes that are poorly understood, the ATM protein signals DNA damage to TP53, resulting in increased concentrations of the p53 tumour suppressor protein, which is often described as the 'guardian of the genome'. In its tetrameric form, p53 is a transcription factor normally present in low concentrations through interactions with the MDM-2 protein that signals its degradation (Evan and Littlewood, 1998). When p53 concentrations are raised, progression through the cell cycle is halted, providing time for DNA repair or for initiation of apoptosis. Little is known about why a given cell may respond to DNA damage by growth arrest and repair whilst another responds by inducing apoptosis, but it has been hypothesized that apoptosis would be favoured in cells with a reduced capacity for repair (Liu and Kulesz-Martin, 2001). The most primitive form of p53 identified is that in Drosophila where p53 mediates apoptosis but not growth arrest, which suggests that apoptosis signalling was the earliest role for p53 (Liu and Kulesz-Martin, 2001). p53-independent apoptosis appears to play a role in prevention of teratogenesis by facilitating DNA
repair or causing fetal death (Norimura etal., 1996). TP53 is the gene most frequently mutated or lost in tumours, which indicates its central role in protection of the genome. More than 50% of human tumours contain a mutated TP53, with most of those mutations (>90%) being missense mutations within the evolutionarily conserved DNA-binding domain (Hollstein et al., 1994).
The binding of p53 to DNA occurs by both sequence-specific and non-sequence-specific mechanisms, and is highly dependent upon the reduction state of the molecule since the binding involves a zinc finger and a further seven cysteine residues (Liu and Kulesz-Martin, 2001). Evidence is accumulating that signals from both oxidative stress pathways and DNA strand breaks are integrated by p53 (Liu and Kulesz-Martin, 2001), enhancing its central role in protecting the genome from diet-induced and other forms of damage. It is possible that the familial breast cancer genes BRCA1 and BRCA2 are also involved in the damage checkpoint at G1-S (Strachan and Read, 1999). Evidence is accumulating (Hickman and Samson, 1999) that chemicals that alkylate DNA resulting in the formation of O6-alkylguanine adducts initiate apoptosis using signals from the MutSa branch of the DNA mismatch repair (MMR) pathway and may be independent of the p53 status of the cell. Fishel (2001) has proposed that these MMR proteins function as specific 'direct sensors' linking pathways to DNA repair or to apoptosis.
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