Genetic Cutting and Splicing Disaster

bill nelson
William G. Nelson

Picture a snowball tumbling down a hill. It doesn't just get bigger, it gets more complicated, picking up a rocks, twigs, and other little bits of debris. Something similar happens with cancer. As it advances, it acquires things, too, says oncologist William G. Nelson, M.D., Ph.D., "gene defects that give it the ability to grow uncontrollably, to spread to the bones and other organs, and to threaten life."

One of these genetic events is an unfortunate switching of places of DNA on a chromosome — like a LEGO, taken off of one brick and stuck back on another. This particular brick, a gene with the alphabet-laden name of TMPRSS2, is normally regulated by male hormones, or androgens.

But in prostate cancer, it breaks away from its normal site and joins another gene, called ERG, which encourages cancer cells to grow. The unwelcome result of this fusion between TMPRSS2 and ERG is that "prostate cancer cells respond to androgens by exhibiting rapid growth," says Nelson, the Director of the Sidney Kimmel Comprehensive Cancer Center.

In recent work with scientists Vasan Yegnasubramanian and Michael Haffner, Nelson learned more about how this happens. Androgens use an "untangling enzyme," which normally breaks and reconnects DNA with no ill effect, to do the job. Nelson compares how it works to what happens when a cassette tape breaks, and all of the tape spills out in a messy snarl. "One way to untangle the tape is to cut and rejoin the tape segments," he says. "If a segment is cut but not accurately rejoined, then an intact cassette tape can be generated by splicing the end somewhere else, leading to a rearrangement of the recorded material on the tape."



" This DNA mess is like what
happens when a cassette breaks,
and the tape gets all tangled up."

Similarly, the untangling enzyme cuts and splices. In cancer, the enzyme accomplishes the first part of its job — breaking segments of DNA — just fine. However, it doesn't hook them back up, "leaving free DNA ends to plug in haphazardly to other sites in the genome," Nelson says. "This mechanism enables the male hormone, testosterone, to cause genetic damage in prostate cells."


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