Every time a cell divides, it must copy three billion DNA letters accurately—but damage from sunlight or chemicals can stall this process, and a special class of enzymes, called DNA polymerases, is needed to copy past the damage. This matters because people with xeroderma pigmentosum (XP) cannot repair DNA damage from ultraviolet light, and they develop skin cancers at roughly 1,000 times the normal rate. A subset of XP patients, known as XP variants, lack one of these special polymerases. The research aims to understand exactly how these polymerases work inside cells, what goes wrong when they are missing, and how this failure drives cancer formation. If successful, the work could identify these polymerases as targets for chemotherapeutic drugs. Blocking them in cancer cells might make tumours more vulnerable to DNA-damaging treatments, while sparing healthy cells. The research also explores the SMC5-6 protein complex, which helps maintain chromosome structure during DNA repair—a fundamental process whose disruption is linked to genome instability and cancer. This is primarily fundamental science, but similar discoveries about DNA repair enzymes have already led to targeted cancer therapies.
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The genetic information, which determines the precise functions of every cell in the body, is contained in the sequence of the three billion nucleotide bases that make up the DNA molecules in the 46 chromosomes of every human cell. Our DNA is being continually damaged by exposure to carcinogenic chemicals and sunlight. Fortunately, we have evolved a whole series of DNA repair and other damage response mechanisms, to enable us to withstand almost every kind of DNA damage and thereby maintain the integrity of the genome. We know that DNA repair is important for human health because there are several genetic diseases that are caused by defects in one or other of these DNA repair processes. Individuals with xeroderma pigmentosum (XP) are unable to deal with damage inflicted in DNA by ultraviolet light from the sun. As a consequence, they develop skin cancers at a frequency some 1000-fold above that in the general population. Before a cell divides, it must replicate its DNA precisely, i.e. all of the three billion bases must be correctly copied. When DNA is damaged, most of the damage is repaired, but repair can be quite slow, and a rapidly growing cell is faced with the problem of having to replicate damaged DNA. Enzymes that replicate DNA are called DNA polymerases, and there is a recently discovered class of these DNA polymerases, which have special properties that enable them to replicate DNA containing damage. Whereas the majority of XP patients simply cannot remove damage from their DNA, a substantial minority, known as XP variants, is deficient in one of these special polymerases. The aim of this proposal is to understand how these special polymerases work inside the cell, what happens in XP variant cells when one of the polymerases is absent, and what the broader implications are for carcinogenesis in general. These special polymerases might prove to be suitable targets for chemotherapeutic drugs, and understanding how they work will assist in rational drug design. The SMC proteins are a family of proteins that maintain the structure of the chromosomes, during the many complicated transactions that occur in the cell. One of these family members is also involved in repairing DNA damage and we are trying to understand how these proteins work.
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