The classic double helix of DNA is vulnerable to breaks, and when this damage involves both strands, molecular danger lurks in the form of translocations -- the breaking and rejoining of two non-adjacent areas along a chromosome -- often leading to cancer. Radiation and ultraviolet rays from sun exposure can cause these DNA breaks when cells divide and multiply.
Repair mechanism for double-stranded DNA breaks (Roger A. Greenberg, MD, PhD)
Reading of the genetic code to produce RNA, a process known as transcription, creates a particularly dangerous situation when it occurs in the vicinity of these DNA breaks. For example, almost all translocations occur at these reading sites.
Published recently in the scientific journal Cell, Roger A. Greenberg, MD, PhD, Assistant Professor of Cancer Biology at the University of Pennsylvania School of Medicine, and colleagues, found that double-stranded DNA breaks block transcription along extensive regions of the same chromosome, eventually stopping the process up to thousands of bases away from the break. (Base pairs are the fundamental blocks of the genetic code.)
"There is a defined molecular sequence of events that allows this block to happen," says Greenberg. One protein senses the break, helping another protein called ubiquitin mark the breaks along the chromosome. DNA repair proteins then recognize specific parts of the ubiquitin protein, enabling repair of the DNA break ends by joining them together. An interesting observation made in this study is that the transcriptional silencing is reversible. Following DNA repair, cellular enzymes remove the ubiquitin marks allowing transcription to be restored.
However, if the DNA breaks aren't reconnected, or if the ubiquitin tags are not removed, silencing of the DNA code persists. "We hypothesize that this change may become permanent in a person's genome, and eventually able to be passed on from generation to generation," explains Greenberg. "Our work opens up new possibilities for understanding the underlying mechanisms of genetic changes by mechanisms other than alternations to the underlying DNA sequence."
Niraj Shanbhag, an MD, PhD student in the Greenberg lab, and Susan Janicki, PhD, and Ilona Rafalska-Metcalf, PhD, Wistar Institute, were also co-authors.
