Researchers at the University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute (UPCI) reveal that malfunctions in the molecular "proofreading" machinery help explain why people who have the disease xeroderma pigmentosum (XP) are at an extremely high risk for developing skin cancer. This machinery repairs structural errors in DNA caused by ultraviolet (UV) light damage.
Their findings will be published this week in the early online version of the Proceedings of the National Academy of Sciences. Previous research has shown that a DNA-repair protein called human UV-damaged DNA-binding protein, or UV-DDB, signals for a repair when two UV-DDB molecules bind to the site of the problem, said senior investigator Bennett Van Houten, Ph.D., the Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and co-leader of UPCI's Molecular and Cell Biology Program. "Our new study shows UV-DDB makes stops along the DNA strand and transiently attaches to it, causing a proofreading change in the protein's conformation, or shape. If the DNA is damaged the protein stays, if the DNA is not damaged the protein leaves," Dr. Van Houten said. "When it comes to a spot that has been damaged by UV radiation, two molecules of UV-DDB converge and stay tightly bound to the site, essentially flagging it for the attention of repair machinery."