Colorado State University researchers, in a collaboration with Harvard Medical School, have discovered how the Kaposi sarcoma herpesvirus – one of society’s most troublesome virulent diseases – uses a protein to attach itself to chromosomes, allowing the virus to hide within the cells and cause them to be malignant.
The disease, which affects patients infected with Acquired Immune Deficiency Syndrome, or AIDS, is called Kaposi’s sarcoma. The AIDS epidemic has grown among minority populations and is a leading killer of African-American men ages 25 to 44, according to the National Institutes of Health.
The discovery at Colorado State, which appears in "Science" magazine this week, helps scientists understand more about the basic building blocks of chromosomes. The ability to apply a molecular understanding of human genome control mechanisms is anticipated to pave the way for unsurpassed advances in the biological sciences, physics, chemistry and other life sciences areas and could lead to major human health benefits.
Jayanth Chodaparambil, a graduate student, made the finding while working in the Colorado State laboratory of Karolin Luger, a Howard Hughes Medical Institute researcher in the renowned Department of Biochemistry and Molecular Biology. They began their research after Harvard University biologists Andrew Barbera and Kenneth Kaye, who were studying Kaposi sarcoma, contacted Luger’s laboratory to understand more about their recent discovery that the virus attaches itself to core histones.
"It’s really the way science should be done," said Luger, co-author of the article, of the collaboration with Harvard. "We would never have embarked on this line of research alone, and the combination of experimental approaches is unique. I’m really happy for my student."
Luger, who joined Colorado State in 1999, is one of the world’s foremost authorities in nucleosome structure, the basic unit for compacting DNA. She is one of 43 scientists chosen this year as investigators by the Chevy Chase, Md.-based Howard Hughes Medical Institute, an appointment that honors the nation’s most promising biomedical scientists.
In their research, Luger and Chodaparambil and their collaborators found out that the Kaposi sarcoma virus sticks its DNA to the nucleosome through the latency-associated nuclear antigen or LANA protein. This allows the virus to persist inside the cell and force it into making more virus. If a cell divides, the virus must make sure that its genes are also distributed to both daughter cells, and it does so by tethering itself to the host chromosomes.
"No one knew exactly how the virus tethered itself to the host," Chodaparambil said. "Now we know that this protein binds itself to the core of the nucleosome."
At Colorado State, Luger’s research focuses on the structure and function of eukaryotic chromatin. She led an extraordinary scientific breakthrough that effectively solved the three-dimensional structure of the nucleosome. The nucleosome is a spool-like basic building block of chromatin, the material in which possibly billions of DNA base pairs are compacted in an individual cell nucleus. This work is now cited in nearly every modern textbook of biochemistry and molecular biology.
Luger and one of her post-doctoral students, Young-Jun Park, also recently published an article in the journal, "Proceedings of the National Academy of Sciences," about the behavior of ‘chaperone proteins’ around nucleosomes. Almost like human chaperones, these proteins prevent the proteins that make up the nucleosome from improper interactions. The "chaperone" also constantly picks apart the nucleosomes, in some cases taking them apart and reconstructing them. It also acts like a scavenger, sorting through bad or unhealthy nucleosomes, taking them out and replacing them with healthy ones. Park and Luger have now elucidated the three-dimensional structure of such a chaperone, allowing them to speculate how it fulfills its essential function.
Still to be discovered? How the cellular machinery knows which of the roughly 35,000 genes need to be read and translated into protein at any given time, and in any given cell type.
"We don’t know at all how this works," Luger said. "Imagine finding 200 differently colored needles in an enormous tangled haystack in a precise order and in a very short time! It’s really an impossible proposition. We have the information of the human genome, but we don’t know how the information is accessed by cells."