Two papers published in Cell provide the crystal structure of XPD helicase, offering insight into xeroderma pigmentosa, Cockayne syndrome, and trichothiodystrophy.



Two studies to be published in the May 30 issue of Cell uncover the crystal structure and biochemical activity of an enzyme known as XPD helicase taken from Sulfolobus archaea, microbes that share many fundamental genes with humans. One was led by John Tainer, Ph.D., a professor at The Scripps Research Institute, and the other was led by professor Malcolm White of the University of St Andrews.


Point mutations in human XPD, sometimes at neighboring sites, can spell the difference between cancer-prone xeroderma pigmentosa (XP), the aging disorder known as Cockayne syndrome (CS), and another aging disorder called trichothiodystrophy (TTD), according to the researchers.


“If you consider the linear sequence of XPD and map the disease-linked point mutations onto it, there is nothing clear about why they would be causative for one of the three diseases or another,” say one Jill Fuss of The Scripps Research Institute. “By having these structures for XPD, we suddenly see how it is working.”


Both teams now have evidence to explain what separates the diseases despite their similar molecular causes. They found that XP-causing mutations in XPD all fall on sites where the helicase binds ATP or DNA. Those alterations leave the enzyme unable to function in DNA repair. The overall effect on the structure of the enzyme, however, is minimal. As such, the enzyme still fills its position in the TFIIH complex, allowing transcription to proceed. That inability to repair defects leaves those with XP prone to developing cancer as mutations arise and go uncorrected, according to the researchers.


In the case of TTD, the defect is quite different, according to Dr. White. TTD-linked mutations are found all over the protein at points important to its interactions with other proteins. Therefore, those mutations destabilizes the entire TFIIH complex and causes defects in both transcription and repair, he continues.


As for CS, Dr. Tainer’s group suggests it results when defects in XPD lock the protein into a rigid position. As a result, they say, the protein may stick in repair mode and cut out DNA at sites where it should be transcribing. Dr. White agrees that CS seems to result from mutations that influence the XPD protein’s flexibility. He is not yet sure, though, exactly how that leads to the symptoms of CS.


The Scripps team also worked with  Lawrence Berkeley National Laboratory and the San Diego Supercomputer Center.








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