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Selfish gene solves DNA replication puzzle

The Dead Sea reveals new growth strategy. ilaufer

Selfish gene solves DNA replication puzzle

You were formed from a single cell. To build you, and then keep you alive, the DNA in your cells needs to undergo replication every day to duplicate your chromosomes before cell division. Decades of research have determined that DNA replication begins at specific locations on the chromosome. These sites are called replication origins. Bacteria have a single replication origin but more complex organisms, such as humans, need thousands of these start sites.

In a paper recently published in Nature, our group at the University of Nottingham has demonstrated that not only are these start sites unnecessary, but that cells grow faster without them. This has implications for understanding the out-of-control DNA duplication seen in cancer cells.

Our research on DNA replication was carried out in the single-celled organism Haloferax volcanii, which is a member of the archaea. The tree of life is split into three groups: eukaryotes (including us), bacteria and archaea. Archaea are microbes best known for living in extreme conditions such as acid pools, hydrothermal vents and salt lakes. H. volcanii originates from the Dead Sea.

We chose H. volcanii because the enzymes that carry out DNA replication in archaea are similar to, but less complex than, those used in multi-cellular organisms. Therefore, understanding a key process such as genome duplication in archaea can inform us about the same process in humans.

We used a type of DNA sequencing to count DNA fragments in replicating cells. Any fragments present in two copies must have been duplicated, and will point to the location of replication origins. We were able to show that H. volcanii uses several origins to replicate its chromosome. But when all of these replication origins are removed, not only are the cells alive, but surprisingly they grow 7.5% faster.

Doing these experiments in human cells would have been impossible. When replication origins are eliminated from eukaryotes or bacteria, it prevents DNA replication and eventually leads to death. So how is H. volcanii able to survive? We found that cells without origins use an alternative method called recombination to begin DNA replication. Recombination is a form of DNA repair, it is normally used to mend breaks in the chromosome.

Why does this lead to faster growth? By using DNA sequencing, we showed that recombination is able to begin DNA replication at all locations on the chromosome with equal efficiency. In other words, it is not restricted to a limited number of sites such as replication origins, and this makes the process faster. But this poses a puzzle: if the alternative process using recombination is more efficient, then why have replication origins at all?

In our paper we suggest that replication origins in H. volcanii are an example of a selfish gene. Selfish genes need not offer any advantage to the host organism, they can even be detrimental to its fitness. But they increase their own gene frequency because they are duplicated along with the rest of the genome. In this case, the origin has hijacked the DNA replication machinery to ensure their own survival.

Why does this matter? The unusual mechanism of DNA replication we have discovered in H. volcanii has parallels with cancer. The organism has multiple copies of its genome and helps the organism survive without regulated DNA replication. Many cancer cells have mutations in the genes that control DNA replication, and multiply genome copies are a common feature of cancer cells.

Another consequence of unchecked DNA replication is that cancer cells grow faster than ordinary cells, which can lead to tumours spreading throughout the body. This accelerated growth is reminiscent of originless H. volcanii, which use alternative mechanisms of replication to outpace other cells.

Our work on a microbe from the Dead Sea has shown how surprising results can come from testing long-held assumptions in unusual organisms. But the work has given us more questions than answers. How exactly does this alternative mechanism of DNA replication work? Does H. volcanii use it all the time? How widespread in nature is this mechanism? Work on this process may contribute to our understanding of how cancer cells evade the normal checks on DNA replication.