3D virus cells attacking a DNA strand
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The Merkel cell polyomavirus (MCV), usually harmless in most infected people, causes an aggressive skin cancer called Merkel cell carcinoma in about 3,000 people each year. New research published in PNAS from the University of Pittsburgh reveals the first steps explaining how the virus outpaces replication of its host cell, ultimately leading to cancer development. Their discoveries suggest these replication steps may be used by other cancer-causing viruses and may ultimately yield new treatment targets.

In 2008, the group first discovered that MCV was the cause of Merkel cell carcinoma. “The underlying reason for this new study was to get a better understanding of what the very first steps were that are required for a healthy cell that’s infected by MCV to become a cancer cell,” explains co-senior author Patrick Moore, MD. In their new paper, the researchers learned how the virus uses differential replication cycles to integrate its contents into its host causing it to become cancerous.

During normal cell division, the first step of DNA replication involves proteins called helicases that form two sleeves around the DNA double helix. These sleeves push together to unzip the double-stranded DNA into single strands so that other proteins can bind and perform the next steps. This unzipping process requires cellular energy in the form of the molecule ATP.

“But when the virus begins to replicate it does so in an uncontrolled fashion and it is more likely to make mistakes and integrate into the host genome by accident,” says Moore. “That’s how this cancer can occur. And that’s the reason why when a cell is replicating this virus, it’s at risk for becoming a cancer cell because these mutations can occur due to the way that the virus replicates.”

The host cell replicates its DNA in a much more cautious way so that it only replicates its DNA once and only once during a given cell cycle when the cells divide from one cell into two cells.

“Viruses don’t behave that way since they’re in a state where they’re going to kill the cell. By just replicating hundreds of virions within the cell they don’t really need to be cautious in how they replicate their own DNA,” adds Moore.

This unchecked replication is not subject to the same quality control and is much more prone to errors. With MCV, certain mutations can cause the virus’s entire genome to get inserted into its host’s genome, causing previously normal cells to undergo uninhibited growth and division to become cancerous. When the virus hijacks a host cell’s DNA replication machinery, it replicates hundreds of times without expending any energy.

The Pitt team found that MCV’s version of helicase does not form sleeves around the DNA as they had expected. Instead, it directly pries apart the DNA molecule. The viral helicase can do this repeatedly without using ATP, enabling the virus to outcompete normal cellular replication.

“The virus ‘melts’ its own DNA and allows it to take over the host cell machinery,” says Moore. “That puts that cell at risk to become a cancer cell that can kill someone.”

The researchers believe these discoveries in MCV provide a broad idea of how viruses outcompete the host cell because they use much of the same machinery to replicate themselves.

In particular, the team hopes this new information could eventually lead to new antiviral therapies, not for MCV because it’s usually harmless, but for closely related viruses such as those known as JC and BK that are major problems for transplant patients or for other cancer-causing viruses.

In addition to MCV, six other human viruses are known to cause cancer, including human papillomavirus (HPV) that causes cervical and head-and neck cancer and Kaposi sarcoma herpesvirus—also discovered by the Pitt team—which causes a type of cancer that forms in the lining of the blood and lymph vessels.

“Knowing how this helicase works can give us clues how those viruses replicate, and medicines that would target them and could potentially give us a very powerful antiviral that could prevent those diseases,” says Moore.

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