A rudimentary form of life that is found in some of the harshest
environments on earth is able to sidestep normal replication processes
and reproduce by the back door, researchers at The University of
Nottingham have found.
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| Haloferax volcanii [Credit: © The Eichler Laboratory] |
The study,
published in the journal Nature, centers on Haloferax volcanii — part of a family of single-celled
organisms called archaea that until recently were thought to be a type
of bacteria.
The findings, led by scientists from the University’s School of Life
Sciences, could offer new insights into how defective cells can multiply
out of control in diseases such as cancer.
Their discovery comes in the same year as the 50th anniversary of a
landmark in the field of DNA replication — the presentation of the
replicon model at the Cold Spring Harbor Symposium on DNA Replication in
1963 by François Jacob, who was later awarded the Nobel Prize in
Medicine.
Dr Thorsten Allers said: “Sadly François Jacob passed away this year,
but 50 years after this theory was presented it still guides the
investigation of DNA replication.
“Given this anniversary, our paper in Nature is rather timely. We have
shown that in some organisms, the replication origins — genetic switches
that control DNA replication — are not only unnecessary but cells will
actually grow faster when these origins are not present. This is totally
unexpected and has forced us to re-evaluate one of the cornerstones of
DNA biology.”
The paper, Accelerated Growth in the Absence of DNA Replication Origins,
was co-authored by Dr Thorsten Allers, Dr Conrad Nieduszynski and Dr
Michelle Hawkins in the University’s School of Life Sciences in
collaboration with Dr Sunir Malla and Dr Martin Blythe in DeepSeq, the
School’s state-of-the-art DNA deep sequencing laboratory.
Archaea were originally discovered in extreme environments and can
survive at very high or very low temperatures, or in highly salty,
acidic or alkaline water. They form one of the three distinct branches
of life along with bacteria and eukaryotes, which are multi-celled
organisms including humans, other animals, plants and fungi. At a
genetic level, archaea have been found to be more closely related to
eukaryotes, and therefore humans, than to bacteria. The salt-loving
Haloferax volcanii being studied by the Nottingham scientists originates
from the Dead Sea.
Dr Allers added: “Although they look like bacteria and behave like
bacteria, archaea are actually more closely related to us. Where we
really see the similarities is when we look at the enzymes that are
responsible for DNA replication and that’s why we thought this would be
an interesting system to work on. We’ve got something that’s life but
not as we know it: on the outside they look like bacteria but on the
inside they look like us.”
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| Dead Sea salt formations near Ein Gedi Nature Reserve, Israel [Credit: © The Eichler Laboratory] |
“What we’ve discovered is that in this type of archaea, François Jacob’s
replicon model, which was proposed 50 years ago and was thought by
everybody to be absolutely fundamental to life, is not necessarily
true.”
In order to reproduce, all life forms need to copy their DNA before the
cell can divide. They do this via a series of ‘replication origins’ that
are located around their chromosomes and to which proteins bind in
order to start the replication process.
In eukaryotes such as humans if these replication origins are eliminated
it prevents replication and eventually leads to cell death.
However, the Nottingham study, funded by the Biotechnology and
Biological Sciences Research Council (BBSRC) and the Royal Society,
found that the Haloferax volcanii is able to spontaneously begin a chain
reaction of replication all around its chromosomes even when its
replication origins have been eliminated.
In addition, the scientists discovered that far from being disadvantaged
by having to employ this novel survival method, the archaea without
chromosomal origins grew faster.
“The amazing thing that we found wasn’t just that deleting the origins
still allowed the cells to grow, but that they now actually grew almost
10 per cent faster. Everybody was thinking, ‘where’s the catch?’ But we
haven’t found one” Dr Conrad Nieduszynski said.
“The way cells initiates this replication process is to use a form of
DNA repair that exists in all of us, but they just hijack this process
for a different purpose. By using this mechanism, they kick-start
replication at multiple sites around the chromosome at the same time.”
Since it appears that origins are unnecessary in Haloferax volcanii, the
scientists believe that replication origins in this organism could be
an example of a ‘selfish gene’ — benefiting the origins by offering the
chance to be continually replicated while offering no advantage to the
organism itself.
For humans it is very important that we can regulate this process of DNA
replication to ensure that our chromosomes are only copied once before
the cell divides, otherwise this can lead to genetic diseases including
cancer.
When cancer cells develop they no longer regulate the copying of their
genome — this happens because of mutations in the genes that control
this process. Loss of replication control leads to cancer cells making
more than just two copies of their chromosomes, which is something they
have in common with what the scientists observed in Haloferax volcanii.
Dr Allers said: “Scientists think that cancer cells revert back to a
more primitive state without these forms of control. This is how they
resemble Haloferax volcanii. One of the other hallmarks of cancer cells
is that grow faster than ordinary cells and can quickly take over the
body. This is similar to what we are seeing — when you don’t regulate
DNA replication and dispense with the normal checks and balances, you
can have unregulated, faster growth.”
In the future if we can understand this mechanism it could give us an
insight into how cancer cells can escape normal regulation and control.
It could even identify new targets for killing cancer cells without
harming normal cells.
