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The human body’s natural response to prevent skin cancer may also hinder cancer treatments from working, a twist of fate that UNC pathologist William Kaufmann and his collaborators uncovered.
Kaufmann’s team demonstrated that two cellular proteins — Tipin and Timeless — help slow the rate of DNA replication. This slowdown gives cells additional time to repair DNA that ultraviolet radiation has damaged. It is this damage, or cellular mutation, that if left untreated could lead to skin cancer, a disease that affects one million Americans each year.
The slowdown of DNA replication, of course, is a good thing; it’s nature’s way of protecting the body from cancerous growths.
“But the protective response may make some cells more resistant to certain types of cancer therapy, such as radiation treatment and chemotherapeutic agents, which work by inducing the cancer cell to die,” Kaufmann said. “If a cancer cell is given this additional time to recover from treatment, it may be able to survive the treatment, much to the detriment of the patient.”
Kaufmann said that scientists have known for 25 years that cells can keep DNA from starting to replicate when cells detect damage in their own DNA, but only in the past several years have researchers been able to understand why.
And only now, thanks in part to UNC researchers, have scientists shown that DNA replication already under way can be slowed down because of Timeless and Tipin.
UNC’s team includes several scientists who contributed key findings. Pathologist Paul Chastain developed a way to label DNA molecules with fluorescent colors so scientists can study what happens to different DNA molecules under various conditions. Biochemist Keziban Unsal-Kacmaz, who since has left UNC, created chemical reagents that reduce the effects of Timeless and Tipin within cell nuclei.
As a team, the researchers learned what happens to DNA when Timeless and Tipin are suppressed in cells exposed to very low doses of ultraviolet radiation.
If Tipin’s effect is suppressed, then the effects of Timeless are completely stopped; if Timeless is taken out, then Tipin’s power to slow replication is reduced, but not completely. But if the two proteins are left to their own devices, they can help slow down or stop DNA replication, allowing cells to repair damage and thereby resist cancer treatment.
“These are the kinds of things we would want to inhibit when applying chemotherapy or radiation to cancer cells because taking out this system will make killing cancer cells more effective,” Kaufmann said.
In an unrelated skin cancer study, UNC researchers led by dermatologist Nancy Thomas found that skin cancer patients who were exposed to a lot of sunlight early in life are more likely to have a gene mutation that is different than the gene mutation caused by sun exposure later in life.
This epidemiological study indicates that patients with melanomas that contain the BRAF gene mutation — found in about half of all melanomas — were more likely to have been exposed to high levels of ultraviolet radiation before age 20.
People with the NRAS gene mutation — found in about 15 percent of melanomas — were more likely to have been exposed to high levels of sunlight between the ages of 50 and 60.
This preliminary study included 214 melanoma patients. Ultimately, the study will include more than 1,000 patients from the United States and Australia.
Thomas said that this research should help with the development of target skin cancer drugs and bolster current recommendations to protect children from too much sunlight.
Editor: Neil Caudle
Writer: Mark Derewicz