Despite all the hype about global warming, sunlight still cheers most of us up. But for a few individuals, who suffer from a rare genetic disorder, sunshine is a serious health hazard. So-called 'children of the night' share no such sun-filled pleasures with the great majority. One in 250 000 people worldwide --- who suffer from Xeroderma pigmentosum (XP) --- are two thousand times more likely to get skin cancer than the rest of us.
Also known as 'moon children', because complete protection from sunlight would only be afforded by an astronaut's suit, when exposed for even a few moments to normal ambient light intensities their skin can severely blister causing skin tumours. Trips outside require serious gear, including powerful UV-masks, caps and gloves.
Waves of ultraviolet radiation streaming forth from the sun range from 100-400 billionths of a metre (nm) in length, on the whole posing little risk for humans. But at a wavelength of around 300nm, they can zap through skin into cells causing chemical mayhem. DNA strands stick together where they shouldn't, hampering replication and running the risk of mutation. In healthy individuals the chaos is quelled by a process called nucleotide excision repair (NER).
Lesions from light
"Individuals with XP cannot repair UV-damage to DNA owing to defects in NER," explains Alan Lehman (University of Sussex, Brighton, UK), expert in DNA repair disorders. The consequences of the disorder range from a generous freckling in some sufferers to extremely severe skin lesions leading to cancer in others. "With no protection," he warns, "XP sufferers will get thousands of skin cancers." Although there is no cure, protection is an effective prevention. However, "patients protected from skin cancers could still die from neurological abnormalities."
"I' ve known patients, wheelchair bound and unable to speak by the age of 16, that have died before reaching 30. Quite a lot of sufferers in this country have neurological abnormalities depending on which gene is mutated," Alan confirms. To inherit XP, mutant genes must be inherited from both parents. Mutations can arise in one of about eight genes that make proteins involved in NER, compromising the cell's ability to cope with daily UV-induced wear and tear and in some cases seriously messing up normal development.
The NER pathway replaces damaged chunks of DNA in a cut and paste manner. Damage is recognized by one or more proteins (including XPC and XPA), which assemble at the damage site. DNA is unwound by a massive protein-enzyme called TFIIH (made in part from XPB and XPD proteins). This produces a 'bubble' from which the damaged area is cut out by the XPF and XPG proteins. Fresh DNA is then synthesized by special polymerase enzymes (delta and epsilon), before another enzyme (a DNA ligase) glues the repaired patch into the DNA backbone.
Weak links at different nodes in the repair system are reflected by varied sets of symptoms between XP patients. Mutations in XPA, which directs repair troops to DNA damage, seem to cause the most severe symptoms, neurological problems arising in early childhood and supersensitive skin leaving patients completely open to skin cancer. Knocking out XPA obliterates the repair process, whereas some other defects in the pathway don't seem to be quite as debilitating.
The whole NER system relies on the integrity of over 30 proteins, defects to any of which compromise repair in different ways. Faulty NER systems have been found in a number of other rare syndromes including TTD (trichothiodystrophy). The features of this syndrome, sulphur-deficient brittle hair and scaly skin, have little in common with XP. Patients' cells are sometimes sun-sensitive, but there is no increased risk of skin cancer, although premature ageing is pronounced. Getting a feel for how NER-malfunction can cause such different syndromes has been a significant challenge. Mouse models have been very revealing in this respect.
Jan Hoeijmakers (Erasmus, Rotterdam, Holland) and his team have created mice with specific mutations in DNA repair genes. One such model mimics a specific mutation observed in human TTD patients, a mutation in the XPD gene that affects a single amino-acid in the protein (De Boer et al 1998 Moll Cell 1:981-990). Mice bearing the same defect have very similar features: brittle hair that grows and breaks, falling out and leaving bald patches. They die young, like their human counterparts, and have a curved spine, wizened appearance, grey hair and wasted limbs.
Defects in XPD are frequently found in XP patients. How do mutations in the same gene result in premature ageing in TTD patients, but susceptibility to skin cancer in XP patients? Jan's feeling is that the answer lies in the triple function of this protein. While XPD is a cog in two distinct DNA repair pathways, as part of the TFIIH enzyme, it also participates in transcription . His hunch led him to question whether brittle hair might result from defects in the transcriptional role of XPD, with skin cancer and premature ageing the result of compromised repair in the other two pathways.
Sure enough, some mutations in XPD have been found to compromise repair, leading to cancer and XP, while closer inspection of mutant cells from humans with TTD reveals subtle defects in transcription. So there is a clear link between genetics and physical characteristics, although not all cases of human disease can be easily related to underlying genetics.
Many challenges remain for scientists who are trying to translate molecular truth into clinical practice. There are no treatments for XP or TTD. Such genetic faults run throughout the entire organism, pervading every cell. However, understanding these diseases stands to benefit us all. "Everyone wants to know when we will cure cancer," says Alan, "but studying these rare genetic diseases is fundamental to understanding how DNA repair works, which will help us to fight cancer."
Texts by Brona McVittie, Science Writer, London, UK. | Figure: Sun isn't good for us all (source)
