New DNA discovery could help in fight against cancer

A new discovery into DNA could prove useful for developing new treatments against aggressive forms of cancer.

Researchers from the University of Copenhagen’s Faculty of Health and Medical Sciences have discovered that our cells replicate their DNA much more loosely than previously thought.

The team inhibited the essential gene DNA polymerase alpha (POLA1), to see how DNA replicates during cell division. Through this method, the researchers discovered that cells can both survive and multiply under more stress than previously thought. More so, the discovery could give the team a new way to fight cancer

Research leader and associate professor Luis Toledo of the Center for Chromosome Stability at the Department of Cellular and Molecular Medicine explained: “If we are visionaries, I would say that we might be at the birth of a whole new set of molecules that could be used in fighting cancer." 

“Basically, if we turn the finding on its head, this novel strategy aims at exploiting an in-built weakness in cancer cells and make them crash while they divide.”

When cells divide, their double DNA strand is opened lengthwise, in way which the researchers describe as being ‘like a zipper that is unzipped’.

Before the new halves of the zipper are made, a bit of DNA is temporally exposed in single stranded form. This process is required for the new zippers to form. Nevertheless, large amounts of single-stranded DNA have traditionally been considered by researchers to be a sign of pathological stress during cell proliferation.

The researchers however, discovered that DNA unzippers act more loosely than expected – generating large amounts of single-stranded DNA that show no more than a form of natural stress, that cells can tolerate high quantities.

Still, for this tolerance to exist, cells require a sufficient amount of the protective protein RPA to cover the single-stranded DNA parts.

“We have seen that cells can duplicate their genome, even with large amounts of single stranded DNA. They can divide and go on living healthily because they have a large excess of RPA molecules that acts as a protective umbrella,” says the study’s first author and former postdoc at the University of Copenhagen Amaia Ercilla.

“But there is a flip side of the coin. When we make the cells generate single strand DNA faster than what they can protect, chromosomes literally shatter in hundreds of pieces, a phenomenon we call replication catastrophe. We always thought that we could use this for instance to kill cancer cells."

Under normal circumstances, the researchers explain how it is extremely difficult to deplete a cell’s reserve of RPA.

However, the team found what they call ‘the ultimate single-stranded DNA generator' which when inhibited with POLA1, was able to deplete a cell’s RPA reserve in just five minutes.

“Although no new DNA can be made when we inhibit POLA1, the DNA unzippers keep advancing and generate single-stranded DNA at very high speed,” professor Toledo said.

With cancer cells being sensitive to POLA1 inhibitors, Toledo speculates “that the strategy could be especially useful against very aggressive forms of cancer that proliferate at a high pace”.

The team’s next step is to find more molecules that biologically inhibits the POLA 1 gene, which when combined with other substances, may be used in the treatment of cancer patients.