5 April 1999. Fred Van Leeuwen and his colleagues reported last year that some neurons in Alzheimer's patients
contain mutant RNA coding for APP and ubiquitin, despite the fact that
the DNA from which the RNA had been transcribed was not mutated. By what
process could "clean" DNA produce "dirty" RNA?
One candidate is a phenomenon called transcriptional bypass, wherein
damage to the template DNA goes uncorrected and becomes responsible for
coding an erroneous base into the RNA. This can happen if, for example,
the DNA base cytosine is deaminated, producing the aberrant base uracil.
Rather than correcting this error, the transcriptional machinery treats
uracil as the proper, and structurally similar, base thymine. Adenine,
rather than the appropriate base, guanine, is then transcribed into the
RNA, introducing an error that is propagated into protein production.
Transcriptional bypass has been demonstrated in vitro, where it can
efficiently generate mutant proteins, but Viwanathan and colleagues have
just published the first demonstration of this process in vivo (Science
2 Apr 1999). Working in mutant E. coli cells that are unable
to correct DNA mutations containing uracil, they were able to transfect
uracil into the cell DNA and show that the cells would transcribe the
gene (for the fluorescing protein luciferase) and produce an altered
protein. In their discussion, the authors point specifically to the work
of Van Leeuwen and colleagues, suggesting that transcriptional bypass
could account for the mutant RNA coding for APP in Alzheimer's patients.-Hakon Heimer.
(See an accompanying editorial by Bridges in the April 2 issue of
Science for discussion of these findings. Read also the Online
Journal Club discussion with Van Leeuwen and colleagues.)
Reference:Viswanathan A, You HJ, Doetsch PW. Phenotypic change caused by transcriptional bypass of uracil in nondividing cells. Science 1999 Apr 2;284(5411):159-62. Abstract
Bridges BA. Dirty transcripts from clean DNA. Science 1999 Apr 2;284(5411):62-3. Abstract