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Patients with the DNA-repair disorder xeroderma pigmentosum (XP) suffer from a wide range of symptoms; some are mild, such as excessive freckling after sun exposure, whereas others are more severe, including skin cancer and neurodegeneration. Genetic variation underlies this heterogeneity, argue Ueda and colleagues.
The so-called “causative” XP mutation (R683W) lies within the transcription complex TFIIH, which helps to transcribe nearly all genes and to repair damaged DNA. The complex includes three subunits with separate enzymatic functions. The R683W mutation is in the XPD subunit and disrupts helicase activity.
XP patients can be homozygous or heterozygous for the R683W mutation. And some heterozygotes bear secondary mutations on the opposing XPD allele. Contrary to popular belief, Ueda et al. suggest that these additional mutations matter. Patients with different secondary mutations had different XP symptoms. And their secondary mutations had a variety of molecular outcomes, ranging from the deletion of an amino acid to the production of a truncated protein.
The authors found that different allelic combinations interfered with TFIIH's repair and transcription cascades in unique ways. Some combinations hampered DNA repair by weakening a link between XPD and another subunit of TFIIH, which decreased XPD's helicase activity. Other mutations indirectly disturbed the function of kinase required for the phosphorylation and activation of RNA polymerase II.
Ueda and colleagues thus suggest that secondary XPD mutations can either enhance or counteract clinical symptoms. Exactly how the nuances in XPD function dictate specific symptoms is not yet clear, and many more XPD mutations remain to be investigated.