The stretches of DNA between genes, littered with repeating sequences, were once considered the “junk of the genome,” but scientists are learning that some of this junk is far from harmless clutter.
Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center report in the journal Cell Reports that certain short, repetitive sequences of DNA, or “junk,” play an important role in the development of Ewing sarcoma, a rare bone and soft tissue cancer that occurs most commonly in children and adolescents.
“Some people may still think of these non-coding sequences as junk; that they don’t really do anything but act as hangers-on to the more famous parts of the genome,” said the study’s senior author Ian J. Davis, MD, PHD, a pediatric oncologist and researcher at UNC Lineberger and the Denman Hammond Associate Professor in Childhood Cancer at the UNC School of Medicine. “But we found that repetitive elements contribute to cancer development for Ewing sarcoma based on traits that they share with immature cells.”
For most people with Ewing sarcoma, their tumors have a mutation that creates a new gene called EWSR1-FLI1. This gene codes for a mutant protein, called an oncoprotein, that drives the cancer. But it turns out that the mutant protein does not work alone.
UNC Lineberger researchers found that specific states of DNA have enhanced susceptibility to the oncoprotein’s attack. In particular, the way that repetitive DNA sequences interact with a class of proteins called histones, which act like a spool around which DNA is wrapped, offer an opportunistic environment for the oncoprotein. At certain sites, the DNA is more “open” or unwrapped around the histone spools, making them more accessible to the oncoprotein.
Davis and his collaborators discovered that the way certain repeat DNA sections interact with histones in Ewing sarcoma bore a striking similarity to that of stem cells, which are cells that haven’t matured and can still become many types of cells. They believe that the looseness in the way that DNA and histones interact in stem cells and cancer cells at these repeat sites allows the oncoprotein to interact with the DNA, changing the way that many genes are expressed.
“We identified a new feature in the way the genome is organized in stem cells, and this ended up explaining a link between these immature cells and the development of Ewing sarcoma,” Davis said. “This is one way we think the oncogene capitalizes on a pre-existing environment and offers some insight into why the cancer might have a very specific window during which it could develop. It’s kind of like a seed and soil relationship. The oncoprotein ‘seed’ can only form cancer in the correct stem cell ‘soil.’”.. Read More>>
Source: Medical Xpress
