12:37pm Tuesday 25 September 2018

U-M discovery helps build a better target for anticancer drug discovery

ANN ARBOR—In one of many ways cancer attacks the body, it activates an enzyme that is typically absent in normal, healthy cells.

The enzyme is also present in stem cells. When stem cells in our bodies divide, chromosomes within those cells, which carry our genetic material, shorten. If they become too short, they can lose that precious genetic material.

An enzyme called telomerase keeps the chromosome healthy by adding DNA to the ends of chromosomes. However, most normal cells in our body don’t divide and so do not have telomerase. This prevents unwanted cell division and cancer growth.

But cancerous cells often activate telomerase, causing the cells to divide ceaselessly, a hallmark of cancer. Now, University of Michigan researchers have identified a region on a protein called TPP1 that binds this enzyme, which could provide a target for anticancer drugs.

“The reason we need this enzyme is because stem cells are these cells in our body that need to keep dividing throughout life to give rise to new cells,” said U-M researcher Jayakrishnan Nandakumar, lead author of the study. “The bad part is that we know cancer is a reality, and 90 percent of cancers, irrespective of the type, kind, stage, tissue or organ, actually switch on telomerase.”

In order for telomerase to travel to the end of chromosomes and keep them from becoming too short, they require the assistance of a protein called TPP1. As a postdoctoral fellow, Nandakumar, an assistant professor of molecular, cellular and developmental biology, discovered a region on TPP1 that allows the telomerase to bind to chromosome ends. This region is called the TEL patch.

Previously, researchers thought there was only one protein region that binds telomerase to chromosome ends, but now, Nandakumar and his team, including doctoral student Sherilyn Grill and postdoctoral researcher Valerie Tesmer, have discovered a second region on TPP1 that assists in binding telomerase to chromosomes. The team is calling the region NOB, based on its location, the N-terminus of the OB domain of TPP1.

The two regions, themselves composed of amino acids, work together to provide a full platform for telomerase to engage chromosome ends. Initially, Nandakumar discovered the TEL patch because it’s a region researchers see across all mammals—from mice to rabbits to humans to frogs.

But researchers overlooked NOB because it was slightly different in the mouse protein compared to the human protein. Additionally, although mouse TPP1 binds mouse telomerase and human TPP1 binds human telomerase, mouse TPP1 cannot bind human telomerase.

“Because of that observation, we were sure that there must be some region that is not conserved between mouse and human, but is still important for binding telomerase,” Nandakumar said.

That left the NOB region.

To test whether this region was important, the team swapped the NOB section of the mouse TPP1 protein with the human NOB region. Once the NOB sections were replaced, mouse TPP1 began stimulating human telomerase, showing that NOB was crucial in the binding of telomerase. The discovery could help inform years of research that combines anticancer drugs with drugs that shut down telomerase activity.

“Why is it a big deal? It’s a big deal because telomerase is a great anticancer target,” Nandakumar said. “It’s not present in every single cell in the body—and so if you stop telomerase somehow, cancer cells can’t re-elongate their chromosomes, and they would ultimately die.”

Now that the team has discovered where telomerase binds TPP1, they hope to determine the other half of the story—where TPP1 binds telomerase.

 

University of Michigan

 


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