Understanding how the skin cancer virus outcompetes host cell replication

University of Pittsburgh researchers have shown for the first time how Merkel cell polyomavirus (MCV), which causes an aggressive skin cancer called Merkel cell carcinoma, initiates DNA replication in host cells. In the new study, the researchers studied MCV replication in never-before-seen detail using an instrument called a C-trap and a technique called SMADNE.

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.

Known as licensed DNA replication, this controlled process occurs only once each time a cell divides. In contrast, when a virus hijacks a host cell’s DNA replication machinery, it replicates hundreds of times.

This “unlicensed” 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 genetic code, or genome, to get inserted into its host’s genome, causing previously normal cells to undergo uninhibited growth and division to become cancerous. the 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.

Reference: Unlicensed origin DNA melting by MCV and SV40 polyomavirus LT proteins is independent of ATP-dependent helicase activity, Proceedings of the National Academy of Sciences, DOI 10.1073/pnas.2308010120