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CU Researchers Discover Yeast Genes Related To Human Leukemia And HIV

University of Colorado at Boulder

A CU-Boulder research team has found that two genes in common baker's yeast are closely related to a family of human genes associated with a particularly severe type of leukemia and HIV-1, a surprising finding with intriguing biomedical implications.

The genes, known as SAS2 and SAS3, were identified, cloned and compared with known sequences of human genes implicated in the diseases, said Assistant Professor Lorraine Pillus of the molecular, cellular and developmental biology department. Research by the CU-Boulder team indicates the genes encode proteins that repress, or silence, particular pieces of genetic information.

The CU-Boulder discovery is expected to help researchers better understand the causes of acute myeloid leukemia and AIDS and perhaps pave the way for the development of new therapies. "We now have some new insights into mechanisms that may influence leukemia and HIV-1 activity," said Pillus.

A paper on the subject by Pillus and MCD biology doctoral students Cheryl Reifsnyder, Joanna Lowell and Astrid Clarke appeared in the September issue of Nature Genetics, an international monthly journal published in Washington, D.C. Nature Genetics is a sister publication of the weekly science journal Nature.

A companion paper in the Nature Genetics issue by a group of scientists led by David Housman of the Massachusetts Institute of Technology identifies the location of two genes associated with acute myeloid leukemia in humans.

Unlike childhood leukemia, acute myeloid leukemia generally strikes later in life and is more resistant to treatment, Pillus said. Myeloid leukemia and AIDS associated with HIV-1 infection both lead to immune system failures.

Of the 80,000 to 100,000 genes in humans, only 20 percent to 30 percent are active in any single cell type -- the rest are repressed in part through gene silencing, said Pillus. "We now know quite a lot about silencing genes in yeast and fruit flies, but these are some of the first clues to similar silencing genes in humans."

Yeast genes are particularly valuable to researchers trying to understand the mechanisms of human disease, she said. The genes are easily clonable, researchers can "pick apart" important biological processes more easily, and a number of yeast genes have sequences and functions very similar to human genes.

In living organisms, double-helix strands of the genetic material, DNA, are interwoven with clumps of protein material known as histones inside the cell nucleus. Collectively known as nucleosomes, the tiny, ball-like structures make up the basic units into which the DNA is packed, she said.

The mechanism of the two newly described silencing genes by the CU team appears to be linked to acetyltransferases, types of enzymes that move a compound known as acetyl onto proteins. The acetylation of proteins can fine-tune their function by changing their chemical charge, or stability, she said.

The degree of acetylation of nucleosomes influences "how tightly packed the DNA in the cell nucleus is," Pillus said. "If nucleosomes are under-acetylated, they are less likely to be activated."

The CU-Bouder findings on the SAS2 gene complemented the work of the MIT team, which subsequently indicated human gene mutations leading to myeloid leukemia may also be associated with acetyltransferases. "We were able to provide that group with a possible mechanism for the activity because of our discovery of the yeast mutant defects," Pillus said.

Many leukemias are caused by a "chromosomal translocation," in which one gene gets fused to another, said Pillus. These translocations, known as "chimeras" by medical researchers, are important for diagnoses of such diseases.

The CU-Boulder research team, including postdoctoral researcher Sandy Jacobson, is conducting a new round of experiments with yeast in which the SAS2 and SAS3 genes are "knocked out" and replaced with their human gene counterparts. As the function of the silencing genes becomes clearer, researchers will intensify their searches for new therapies to halt the diseases.

This is an exciting advance," said Pillus. "Not only do our results suggest a new mechanism for disease, but we can now ask specific questions about potential targets for therapies that could be used to inhibit leukemia and the progression of HIV-1 infection."

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