Researchers find structural basis for incidence of skin cancers in a genetic disorder

June 23, 2010

Researchers from Mount Sinai School of Medicine have found why patients with a variant form of xeroderma pigmentosum (XPV), an inherited genetic disorder characterized by extreme sensitivity to the sun, are more susceptible to skin cancers than the general population. The data are published in the current issue of the journal Nature. Their finding sets the stage for research into therapies that would help protect people with XPV from developing skin cancers.

The research team determined that, in the general population, eta, an enzyme able to overcome the barriers created by and ultraviolet rays and continue replicating DNA strands, is structured differently from any other polymerase. However, in people with XPV, since this enzyme is missing, they are unable to bypass this damage, causing the replication process to stall, resulting in mutations and extremely high susceptibility to skin cancer.

Researchers have never been able to fully determine a structural basis for why the enzyme can get around UV damage. After nearly a decade of research, the Mount Sinai team successfully developed a crystal model, or a three dimensional chemical derivation, of the enzyme. They determined that in the general population, DNA polymerase eta suppresses because the active site, where chemical reactions required to replicate DNA take place, can adjust much better to UV damage than any other DNA polymerase.

"We have been unable to study how DNA polymerase eta can replicate through UV damage because we did not have a crystal structure of the enzyme to study," said Aneel K. Aggarwal, Ph.D, Professor, Structural and , Mount Sinai School of Medicine. "Our team succeeded in developing this structure and determining what makes this enzyme unique."

In conjunction with Drs. Louise and Satya Prakash's group at the University of Texas Medical Branch in Galveston, Texas, Dr. Aggarwal's team generated crystals and analyzed them using X-rays. They determined that the active site of DNA polymerase eta is structured in such a way that it can easily accommodate the UV induced DNA lesions and replicate through them.

"Now that we know the structural basis for the suppression of skin cancers by this , one question for the future is if there's a way to restore its function in people with XPV and reduce their risk for cancer," said Dr. Aggarwal.

According to the National Center for Biotechnology Information of the National Institutes of Health, xeroderma pigmentosum is an inherited characterized by severe sun sensitivity resulting in blisters and precancerous freckles, benign tumors on the skin and eyes, blurry vision and eye pain from atrophic eye lids, and neurologic symptoms including cognitive decline.

Related Stories

Recommended for you

Engineered protein treatment found to reduce obesity in mice, rats and primates

October 19, 2017
(Medical Xpress)—A team of researchers with pharmaceutical company Amgen Inc. report that an engineered version of a protein naturally found in the body caused test mice, rats and cynomolgus monkeys to lose weight. In their ...

New procedure enables cultivation of human brain sections in the petri dish

October 19, 2017
Researchers at the University of Tübingen have become the first to keep human brain tissue alive outside the body for several weeks. The researchers, headed by Dr. Niklas Schwarz, Dr. Henner Koch and Dr. Thomas Wuttke at ...

Cancer drug found to offer promising results in treating sepsis in test mice

October 19, 2017
(Medical Xpress)—A combined team of researchers from China and the U.S. has found that a drug commonly used to treat lung cancer in humans offers a degree of protection against sepsis in test mice. In their paper published ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Study reveals key molecular link in major cell growth pathway

October 19, 2017
A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which ...

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.