Scientists shed light on a genetic engine of cancer

PHILADELPHIA, Pennsylvania (Reuters) -- HATs and tails may sound more like formal wear than the stuff of cutting-edge genetic research. But scientists said Thursday both are critical to deciphering the genetic secrets of certain cancers.

By subjecting common yeast cells to painstaking molecular analysis, a team of biologists at the Philadelphia-based Wistar Institute have deciphered the structure and function of a tiny active protein belonging to a family of enzymes known as HATs, or histone acetyltransferases.

HAT enzymes activate genes in the nuclei of cells by leaving molecules on the "tails" of genetic proteins. Because the yeast enzyme studied by the Wistar team stimulates cell growth, researchers said understanding how it operates could lead to new drugs to fight cancers such as leukemia.

"This enzyme is like a machine. And what we've discovered is not only the shape of the machine but how its engine works," said Shelley Berger, a Wistar researcher and co-author of a study published in the journal Molecular Cell.

"Because we know how the enzyme works, it could help us to rationally design drugs that might inhibit its function."

The 108-year-old Wistar Institute is a nonprofit biomedical research institution dedicated to studying the basic mechanisms that underlie major diseases, including cancer and AIDS. Its scientists are responsible for current vaccines against rabies and rubella.

The latest study, funded by the National Institutes of Health, used X-rays to compose a three-dimensional image of the structure of a yeast protein called Esa1, which is similar to human enzymes implicated in the spread of leukemia and even HIV, the virus that causes AIDS.

By determining the tiny protein's structure, scientists were also able to figure out how it functions.

"Their modes of action are very similar. But there are also subtle differences we can exploit," said Ronen Marmorstein, a Wistar structural biologist and the study's senior author.

The enzymes act on histones, which are small proteins around which DNA coils to form structures called nucleosomes. Compact strings of nucleosomes form chromosomes, 23 pairs of which exist in every human cell.

Researchers say HATs activate genes by adding a molecule to a tail-like structure on the histones. That causes the DNA coil to relax, enabling the gene to operate. Histone deacetylases remove the molecule, causing the DNA to tighten and repressing genetic expression.

Wistar scientists said they work with common brewer's yeast because yeast cells are cheap and grow far faster than human cells, enabling studies to track the effects of genetic modifications in a fraction of the time.

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The Wistar Institute
The Journal Molecular Cell

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