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Researchers at Uppsala University and Harvard University have
collaboratively developed a new theoretical model to explain how
proteins can rapidly find specific DNA sequences, even though there are
many obstacles in the way on the chromosomes.
In living cells, DNA-binding proteins regulate the activity of
various genes so that different cells carry out the right tasks at the
right time. For this to work, the DNA-binding proteins need to find the
right DNA site sufficiently quickly. The research team behind the new
study has previously succeeded in determining that it takes only a few
minutes for an individual protein molecule to look through the millions
of nearly identical binding alternatives and find the right place to
bind. This is nevertheless slower than what is predicted by the
established theoretical model for how DNA-binding proteins find their
way to the proper place by alternating between diffusing in the cell
cytoplasm and along DNA strands.
"By also taking into consideration the fact that there are many
obstacles in the way when proteins are to diffuse along DNA strands, we
can now calculate more exactly how long it takes them to find their
way," says Johan Elf, associate professor of molecular biotechnology at
the Center for Bioinformatics.
Besides offering a more precise prediction regarding the time needed
to find the right site on DNA, the new theoretical model explains why
there is an optimal total concentration of DNA-binding proteins. If
there were more, it would simply be impossible for them to find a
binding place in a reasonable time, since the proteins would be in each
other's way. If there were fewer it would go slower as well, since not
enough proteins would be searching. Finally, the new model provides an
explanation why so many DNA-binding proteins also bind auxiliary
binding sites close to the regulatory site, thus forming DNA loops. It
turns out that this can shorten the time to find the right sites.
"This more detailed understanding of gene regulation is important,
since it can ultimately provide a better understanding of diseases that
occur as a result of problems in the control functions of cells, such
as in cancer" says Johan Elf.
The researchers behind the study are Gene-Wei Li, Otto G. Berg, and
Johan Elf. The findings are being published March 16 in the scientific
journal Nature Physics.
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