Life is full of choices, and even cells come to a fork in the road. They have to decide what to do about damage to their DNA: repair the damage, force the damaged cell to die, or allow the damage to transform the cell to a tumor cell.
A UNC team reports that they have identified how the cell makes the decision, discovering which specific proteins together shape the cell’s fate. A specific type of protein (histone) called H2AX can interact with a partner protein called BCLAF1 to regulate DNA repair, in the process acting as a tumor suppressor, or to initiate cell death. Their findings are reported in the July 26, 2012 online edition of the journal Cell Death and Diseases.
DNA damage recognition/repair is a critical step for cancer development, if dysregulated. H2AX is a well-known DNA damage sensor. DNA damage occurs when a cell is exposed to a stressor, such as an environmental exposure, radiation, or a drug. At that point, depending on how severe the damage is, the cell must make a decision. If a cell is heavily damaged, then the cell tries to promote programmed cell death, a process called apoptosis. The cell can also decide to repair the DNA or the damage can remain, starting the cell on a pathway to becoming a tumor cell.
Xian Chen, PhD, associate professor of biochemistry and biophysics in the UNC School of Medicine and study senior author, says, “People have known about the three cellular pathways or decisions, but the mechanisms underlying how that decision was made remain to be discovered. Here, we discovered one pathway and a key protein interaction.“ Dr. Chen is a member of UNC Lineberger Comprehensive Cancer Center and faculty director of the National Cancer Institute Proteomic Tumor Analysis Consortium (CPTAC) at UNC.
“In order to figure out how cells make right or wrong decisions, we started with H2AX. Once H2AX tags DNA damage, it assembles a protein scaffolding to surround the DNA damage site. We found that in order for a cell to make a decision between apoptosis or repair, it recruits a protein called BCLAF1, known as a pro-apoptotic factor, acting like a tumor suppressor. We documented direct evidence that BCLAF1 is an H2AX-dependent tumor suppressor.
“We found that BCLAF1 is an important H2AX interacting protein. Once H2AX senses DNA damage it tends to recruit BCLAF1 to get rid of damaged cells.“
Dr. Chen reports that while their finding relates to all cancers, they and others have observed that this protein BCLAF1 may be more associated with lung cancer. Exploring that correlation will be their next set of experiments.
Other UNC authors are Yuan Yu Lee, PhD, now a research faculty member at California State University- Long Beach; postdoctoral associates Yanbao Yu, PhD, and Harsha Gunawardena, PhD; and research associate Ling Xie, PhD.
The research was funded by grants from the National Institutes of Health ( 1RO1AI064806-01A2, 5R21DKO82706, and NIH/National Cancer Institute U24CA160035-01) and the Department of Energy, the Office of Science DE-FG02-07ER64422.