About DNA polymerase...
January 21, 2015 8:56 PM   Subscribe

Tomasetti and Vogelstein recently published an analysis that suggests the variation in the number of stem cell divisions leads to cancer incidence rates that are higher for tissues with relatively greater numbers of divisions. They recently posted a follow-up which attempts to address some of the counterarguments to their results. Acting on the premise that their work is correct or at least "in the right direction", are there labs or drug companies working on gene therapies that attempt to improve DNA polymerase fidelity (even in model organisms), as a means to one day perhaps reduce cancer incidence in higher-risk tissues? While it is easy through mutagenesis to worsen fidelity rates and increase cancer rates (as has been demo'ed in mice, say) can this aspect be engineered to be improved — that is, what biochemical aspects of (human) DNA polymerase have evolved to control its fidelity rate such that it might be possible to improve upon it?
posted by a lungful of dragon to Science & Nature (3 answers total)
The first mechanism that comes to mind is kinetic proofreading. But the original paper contains the intriguing observation that:
In an antimutator strain of bacteriophage T4 with an error rate less than 10-3 times that of the wild type, most of the base triphosphate is hydrolysed to free monophosphate instead of adding to the growing polymer.
So you could improve fidelity by adding more kinetic proofreading steps, but at the cost of wasting a lot of energy in futile cycling. I guess you could think of it sort of like adding filtration steps - you could get a very pure product if you don't care about a tiny yield.
posted by en forme de poire at 9:21 PM on January 21, 2015

Improving DNA polymerase fidelity is going to cause an awful lot of cells that would otherwise divide and be healthy to instead die, potentially causing tissue damage and developmental defects, particularly in a young growing animal. Less perfect DNA replication is one of the main mechanisms for repairing DNA damage. This isn't my area of expertise but I work with enough DNA damage people to be wary of this idea.
posted by shelleycat at 10:51 PM on January 21, 2015

Though this doesn't directly answer your question about cancer models, it is worth noting that massive amounts of effort have been devoted to improving the fidelity (and other characteristics) of bacterial DNA polymerases for biotechnology purposes. Exploring that literature might help you understand what kinds of alterations to human DNA polymerase would improve fidelity.
posted by juliapangolin at 4:22 AM on January 22, 2015

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