c-Abl Kinase Works in New Way to Help Skin Cells Fix Damage From UV Light
NEW YORK (June 15, 2006) — Every day, skin cells work overtime to make sure exposure to UV sunlight doesn't lead to lingering mutations in DNA that can trigger cancer.
Now, researchers at the Weill Medical College of Cornell University in New York City have discovered more about how that system works.
In the process, they've also found a whole new mechanism of action for one of the cell's most-studied enzymes, called c-Abl.
"This is a really exciting finding — not only do we now have a better understanding of this cellular 'tag-and-repair' mechanism, but we've also uncovered a novel means of activity for c-Abl," says Dr. Pengbo Zhou, associate professor of pathology and laboratory medicine at Weill Cornell Medical College.
His team's findings appear in the May 19 issue of Molecular Cell.
Scientists have long known that cells have their own self-repair systems, especially when it comes to protecting cells from DNA damage caused by ultraviolet (UV) light.
"The cell can't let this damage go unchecked, because that could incorporate unwanted mutations in DNA and trigger dysfunction or malignancy," Dr. Zhou explains.
So, a system tailor-made for UV damage has evolved over time. Key to this system are special "marker" proteins, including "damaged DNA binding proteins" (DDBs). DDBs — as their name implies — bind to DNA at the site of damage as a kind of "flag" that repair is needed. DDBs are so crucial to UV damage repair that some patients who are born with DDB mutations are easily sunburned and develop skin cancer at an early age, characteristic of a disease called xeroderma pigmentosum.
"But DDBs can't sit at the site of DNA damage indefinitely — they have to be removed before the repair part of the process arrives on the scene. Otherwise, they'd literally get in the way, inhibiting DNA repair," Dr. Zhou explains.
Removing DDBs involves the chemical degradation of DDBs. "We wanted to find out how that occurred," Dr. Zhou says.
The new study used biochemical and reverse genetic experiments in the lab to focus on a key player in this removal process, a "ubiquitin ligase" enzyme called CUL-4A.
CUL-4A binds to DDBs and earmarks them with a destruction tag called "ubiquitin," which signals the cell’s protein destruction apparatus to eliminate ubiquitin-marked DDBs.
And that's where c-Abl — one of the most-studied players in cancer research — comes into the picture.
"C-Abl is a tyrosine kinase enzyme that 'modifies' proteins by adding a phosphate group to their structure. It's a process called phosphorylation, and it's particular to kinases," explains study lead author Xiaoai Chen, a postdoctoral fellow in Dr. Zhou's lab. Dr. Chen worked closely with Stanford University's Dr. James Ford to determine how c-Abl affects the cell’s ability to fix damaged DNA.
The researchers discovered that c-Abl works to clear the way for CUL-4A to get onto DDBs once they are parked at the UV-damaged chromosomal sites, allowing CUL-4A to fulfill its role by degrading DDBs and allowing DNA repair to proceed.
But there was one big surprise: c-Abl appears to work its magic without resorting to its most powerful weapon: its phosphorylating kinase activity.
"That's a completely new phenomenon, and a real surprise to c-Abl researchers who've studied its tyrosine kinase activity in literally more than a thousand scientific publications," Dr. Zhou says.
The finding has real implications for cancer treatment. For example, in chronic myeloid leukemia (CML) patients, c-Abl is abnormally active due to its altered chromosomal arrangement in what is called the Philadelphia chromosome. Some of the most effective anti-cancer agents — including the leukemia drug Gleevec — work by suppressing the over-active tyrosine kinase activity of this malignant form of c-Abl.
"However, if you use Gleevec in the UV-repair context, it wouldn't work, because kinase activity plays no role in this newly identified c-Abl function," Dr. Zhou says.
Thus, it appears that c-Abl works in complex ways, depending on the environment. In some contexts — such as after a skin cell is exposed to UV light — c-Abl may help protect us against cancer by ensuring proper repair of DNA damage. But in other situations, such as certain blood cancers, c-Abl's kinase activity is permanently switched on, and actually promotes malignancy.
The DDB "tagging" proteins may lead a "double life," too, Dr. Zhou says.
"DDBs appear to recognize sites of DNA damage by noting the resulting structural changes on the chromosome," he says. "Trouble is, some of these chromosomal changes occur during normal, healthy DNA metabolism. Based on our research, we now believe that c-Abl and CUL-4A work together to prevent DDBs from getting confused by stopping them from interfering with normal DNA processes and pointing only toward spots of damage where repair is needed."
A better understanding of these microscopic — but potentially life-saving — biochemical processes could hold the promise of designing targeted intervention strategies in cancer treatment, the researchers say.
This work was funded by grants from the Susan G. Komen Foundation for Breast Cancer Research and the National Institutes of Health.
Co-authors included Jianxuan Zhang and Jennifer Lee, of Weill Cornell Medical College in New York City; Drs. James Ford and Patrick S. Lin, of Stanford University, Stanford, California; and Dr. Ning Zheng, of the University of Washington, Seattle.
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