Visualizing How Cancer Chromosome Abnormalities Form in Living Cells

Scientists have for the first time directly observed events that lead to the formation of a chromosome abnormality that is frequently found in cancer cells. The abnormality, called a translocation, occurs when part of a chromosome breaks off and then binds to another chromosome.

The study’s findings, conducted by scientists at the U.S. National Cancer Institute (NCI; Bethesda, MD, USA), part of the National Institutes of Health, were published August 9, 2013, in the journal Science. 

Chromosome translocations have been found in almost all cancer cells, and it has long been known that translocations can play a role in cancer development. However, spite of intensive of research, just precisely how translocations form in a cell has remained elusive. To better determine this process, the researchers created a research system in which they induced, in a controlled way, breaks in the DNA of different chromosomes in living cells. Using cutting-edge imaging technology, they were then able to see when the broken ends of the chromosomes were reattached correctly or incorrectly inside the cells.

Translocations are very rare occurrences, and the investigators’ ability to visualize these events in real time was made possible bya recently developed technology that is being used at the NCI that enables investigators to visualize alterations in thousands of cells over a long time. “Our ability to see this fundamental process in cancer formation was possible only because of access to revolutionary imaging technology,” said the study’s senior author, Tom Misteli, PhD, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, NCI.

The scientists involved with this study were able to demonstrate that translocations can occur within hours of DNA breaks and that their formation is independent of when the breaks happen during the cell division cycle. Cells have intrinsic mending mechanisms that can fix most DNA breaks, but translocations at times still occur.

To additionally examine the role of DNA repair in translocation formation, the researchers curbed vital pieces of the DNA damage response processes within cells and monitored the effects on the repair of DNA breaks and translocation formation. They discovered that suppression of one element of DNA damage response processes, a protein called DNAPK-kinase, increased the occurrence of translocations almost 10-fold. The scientists also determined that translocations formed preferentially between prepositioned genes.

“These observations have allowed us to formulate a time and space framework for elucidating the mechanisms involved in the formation of chromosome translocations,” said Vassilis Roukos, PhD, NCI, and lead scientist of the study. “We can now finally begin to really probe how these fundamental features of cancer cells form.”

Related Links:
US National Cancer Institute