The Structure Of XPD Sheds Light On Cancer And Aging

The role of a unique DNA-repair protein in multiple diseases

Berkeley, CA – The protein XPD is one component of an essential repair mechanism that maintains the integrity of DNA. XPD is unique, however, in that pinpoint mutations of this single protein are responsible for three different human diseases: in xeroderma pigmentosum, extreme sensitivity to sunlight promotes cancer; Cockayne syndrome involves stunted growth and premature aging; trichothiodystrophy, characterized by brittle hair and scaly skin, is another form of greatly accelerated aging.

Now, for the first time, researchers at the Department of Energy’s Lawrence Berkeley National Laboratory and the Scripps Research Institute have solved the essential structure of XPD. The structure reveals how discrete flaws in the remarkable architecture of XPD — as seemingly insignificant as a change in either of two adjacent amino acid residues — can lead to diseases with completely different phenotypes, and gives novel insight into the processes of aging and cancer.

The team that solved XPD’s structure was led by John Tainer, a professor in the Department of Molecular Biology and the Skaggs Institute of Chemical Biology at Scripps and a visiting scientist in the Life Sciences Division (LSD) at Berkeley Lab.

“With this exciting work we have helped open the door to understanding how molecular interactions and activities in the cell result in aging — which is too much cell death — or in cancer, where defective cells are kept alive,” Tainer says.

Li Fan of the Scripps Molecular Biology Department performed the x-ray crystallography of XPD at DOE’s Stanford Linear Accelerator Center and the Advanced Light Source at Berkeley Lab. The biochemistry of XPD was assessed by Jill Fuss, a biochemist in Priscilla Cooper’s laboratory in the Genome Stability Department of Berkeley Lab’s LSD, and by Quen Cheng, a Research Associate in the Cooper lab. The team also included Andrew Arvai of Scripps, Michal Hammel of Berkeley Lab’s Physical Biosciences Division, and Victoria Roberts of the San Diego Supercomputer Center at the University of California at San Diego. The researchers report their results in the May 30 issue of the journal Cell.

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