DNA repair stands as the dike between us and the inundation of mutations.
An average cell normally acquires around 50,000 to 500,000 DNA defects per day. This damage occurs during normal metabolic processes inside the cell, but can also occur upon exposure to other sources of DNA damaging agents such as UV light. Whilst this constitutes only a tiny fraction of the human genome, a single unrepaired lesion to a critical cancer-related gene, as just described, can have drastic consequences. Therefore, DNA repair is an important process which constantly operates in cells. If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in cancer or cell death. Therefore, inherited diseases associated with faulty DNA repair result in increased sensitivity to agents that can damage DNA. Diseases of this kind include xeroderma pigmentosum characterised by the development of multiple skin cancers and Werner syndrome that leads to premature aging. More severe forms of accelerated aging are called progeria.
Xeroderma pigmentosum results from an inability to repair UV damage to DNA, leading to the development of multiple skin cancers. Normally, DNA damage from UV light is repaired through a pathway involving the cutting out of the damaged segment of DNA and replacing it with the correct sequence from the opposing strand. However in this disease, certain enzymes needed in this pathway are missing leading to DNA damage not being readily fixed. There are actually eight types of xeroderma pigmentosum resulting from mutations of different genes that alter enzymes in this process. Diagnosis can usually be made by exposing cell cultures of affected individuals with the radioactive nucleotide base thymidine after being exposed to UV light. If the radioactive thymidine is not incorporated into the DNA then this is indicative of their inability to repair the DNA damaged formed by UV exposure.
Naturally, the most important part of managing the condition is reducing exposure to the sun. An episode of an American series called “Extreme Makeover” involved the Pope family with a daughter Shelly who suffers from this disease; after the show Disney World had a special night-time opening (midnight to 4 am) so that affected children could spend time at the amusement park. A series of books by Dean Koontz revolve around the mysterious events in Moonlight Bay that are investigated by the main character Christopher Snow, who suffers from this genetic disorder that forces him to avoid light at all costs.
Progeria (Gr. pro; early, geras; old age) occurs due to mutations in a gene for the protein lamin A which is a component of the nucleus membrane in the cell, though, how this leads to the characteristic features of progeria is still not known. First identified in 1886 by Jonathan Hutchinson and Hastings Gilford, this extremely rare genetic condition, affecting around newborns, leads to characteristics of accelerated aging occurring at around 18-24 months of age with most sufferers dying in their early teens from heart disease or other age-related problems. While the disease can be dominantly inherited most cases appear to be due to a mutation occurring during the early stages of cell division in a newly conceived child or in the gametes of one of the parents, i.e. a de novo mutation.
“The Child Who’s Older Than Her Grandmother” is a UK documentary first screened in 2005, telling the tragic story of Hayley Okines, a six year old girl born with progeria. However, despite this terrible disease, she became a happy and popular child at school and put a lot of energy into raising the awareness of progeria including recording a song with the Kids Choir 2000 in which; all proceeds went to the Progeria Research Foundation.
It has been suggested that the American author F. Scott Fitzgerald could have been describing this disorder in his short novel “The curious case of Benjamin Button” published in 1921 about a child born with features of an elderly man.
Werner syndrome is characterized by accelerated aging with the dramatic and rapid appearance of features associated with normal aging. It is suggested that the altered Werner protein either interferes with the ability of cells to divide normally or that it may allow DNA damage to accumulate impairing normal cell activities. Individuals with this disorder typically grow and develop normally until they reach puberty after which a premature aging occurs involving greying and loss of hair, a hoarse voice, wrinkled skin, and the development of many disorders associated with aging such as cataracts, skin ulcers, type 2 diabetes, atherosclerosis, osteoporosis and some types of cancer.
In the 1996 movie “Jack,” Robin Williams plays a boy named Jack who is affected by Werner syndrome and is trying to live an normal life.