DNA Replication Protein Plays Role In Cancer

The foundation of biological inheritance is DNA replication

This is a coordinated process in which DNA is copied at hundreds of thousands of different sites across the genome at the same time. If the copying mechanism doesn’t work properly, the result may be cells with missing or extra genetic material, a hallmark of the genomic instability seen in most birth defects and cancers.

Scientists at the University of North Carolina School of Medicine have discovered a protein known as Cdt1. This is required for DNA replication and has an important role in a later step of the cell cycle, mitosis. This is a possible explanation why so many cancers possess not just genomic instability, but also more or less than the usual 46 DNA-containing chromosomes.

The new research was published online ahead of print by the journal Nature Cell Biology. It is the first to definitively show such a dual role for a DNA replication protein.

This was such a surprise. We thought this protein’s job was to load proteins onto the DNA in preparation for replication, said Jean Cook, PhD, associate professor of biochemistry and biophysics and pharmacology at the UNC School of Medicine and senior study author. “We had no idea it also had a night job, in a completely separate part of the cell cycle.”

The cell cycle is the series of events that happen in a cell leading to its growth, replication and division into two daughter cells. It has four distinct phases: G1 (Gap 1), S (DNA synthesis), M (mitosis) and G2 (Gap 2). Cook’s research focuses on G1, when Cdt1 places proteins onto the genetic material to get it ready to be copied.

Cook ran a molecular screen to find other proteins that Cdt1 could be interacting with inside the cell. She expected to only find more entities that controlled replication but was surprised to discover one that was involved in mitosis. That protein, called Hec1 for “highly expressed in cancer,” helps to ensure that the duplicated chromosomes are  divided equally into daughter cells during mitosis. Cook hypothesized that either Hec1 had a job in DNA replication that nobody knew about, or that Cdt1 was the one with the side business.

To look at these two possibilities, Cook partnered with Edward (Ted) D. Salmon, PhD, professor of biology and co-senior author who is a Hec1 expert. After letting Cdt1 do its replication job, they interfered with the protein’s function to see if it adversely affected mitosis. Using a high-powered microscope that records images of live cells, they showed that cells where Cdt1 function had been blocked did not undergo mitosis properly.

When the researchers knew that Cdt1 was involved in mitosis, they wanted to pinpoint its role in that critical process. They combined their genetic, microscopy and computational methods to demonstrate that without Cdt1, Hec1 fails to adopt the conformation inside the cells necessary to connect the chromosomes with the structure that pulls them apart into their separate daughter cells.

Cook says cells that make aberrant amounts of Cdt1, like that seen in cancer, can experience problems in both replication and mitosis. One current clinical trial is actually trying to increase the amount of Cdt1 in cancer cells, hoping to push them from an already precarious position into a fatal one.

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