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Clients in the News – Purdue University Identify Enzymes that help fix cancer-causing DNA defects disovered

Mark Hall is also exploring the possibility of using Cdc14 inhibitors to combat deadly fungal diseases in crops.

Purdue University researchers have identified an important enzyme pathway that helps prevent new cells from receiving too many or too few chromosomes, a condition that has been directly linked to cancer and other diseases.

Mark Hall, associate professor of biochemistry, found that near the end of cell division, the enzyme Cdc14 activates Yen1, an enzyme that ensures any breaks in DNA are fully repaired before the parent cell distributes copies of the genome to daughter cells. This process helps safeguard against some of the most devastating genome errors, including the loss of chromosomes or chromosome segments.

“It only takes one cell to start a tumor,” Hall said. “This study gives us a platform for figuring out exactly what these enzymes are doing in human cells and how they impact genome stability and the avoidance of cancer.”

Cdc14 has been linked to DNA damage repair in humans, but exactly how the enzyme helps preserve the genome and which proteins it regulates in this process have not been known.

Hall and his fellow researchers developed a novel method of identifying the protein substrates upon which Cdc14 acts. Cdc14 regulates the function of other proteins by removing phosphate, a small chemical group, from them. Using Cdc14 in baker’s yeast — which is very similar to human Cdc14 — the team studied the activity of the enzyme on a wide variety of synthetic substrate molecules, looking for similar features among the molecules most preferred by Cdc14.

“We were basically trying different keys in the lock to see which would fit the best,” Hall said.

The team identified the most common structural features on molecules targeted by Cdc14 and used bioinformatics tools to pinpoint matching features in yeast proteins. Yen1 proved to be the best match, and further tests confirmed its role as a substrate of Cdc14. Yen1 is the first Cdc14 substrate involved in DNA repair to be identified.

Hall said the remarkable similarity of these enzymes in yeast and humans makes it likely that this method could be used to identify targets of Cdc14 in humans as well.

“Despite belonging to extremely different species, the ‘lock’ in yeast and human Cdc14 enzymes is exactly the same,” he said. “That gives us confidence that we can use this strategy to identify substrates of human CDC14 and how they work to control DNA repair processes and prevent cancer.”

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