Clinging for Dear Life


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Xeroderma pigmentosum is a rare hereditary disease in which sun-damaged skin is unable to mend itself. Its sufferers run a risk of skin cancer that is 5,000 times higher than normal.
Ten years ago, scientists discovered that the genetic defect behind one form of this disease, known as xeroderma pigmentosum variant (XPV), is a mutant version of an enzyme called DNA polymerase eta, which allows the cell to tolerate sun-induced DNA damage without removing this damage from the DNA molecule. In new research published in the Proceedings of the National Academy of Sciences (PNAS), USA, Prof. Zvi Livneh and research student Omer Ziv of the Biological Chemistry Department reveal how XPV cells manage to survive despite having this mutated enzyme – and at what cost.
With help from Nicholas Geacintov of New York University, and Satoshi Nakajima and Akira Yasui of Tohoku University, Japan, the researchers found that at least three other repair enzymes fill in when the mutated version cannot function. Yet even this combined effort of the three substitutes – DNA polymerases iota, kappa and zeta – only manages to do part of the job, increasing the risk of DNA errors 10- to 20-fold. “What’s fascinating about these findings,” says Livneh, “is that they represent an extreme example of the biological drive to preserve life, even when the price is a heavy load of genetic mutation and a high risk of cancer.”
Prof. Zvi Livneh’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; the estate of Lore F. Leder; and Esther Smidof, Switzerland. Prof. Livneh is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research.