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How One Protein Binds To Genes And Regulates Human Genome

Date:
February 11, 2008
Source:
Cornell University
Summary:
Out of chaos, control: Molecular biologists have discovered how a protein called PARP-1 binds to genes and regulates their expression across the human genome. Knowing where PARP-1 is located and how it works may allow scientists to target this protein while battling common human diseases.
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Out of chaos, control: Cornell University molecular biologists have discovered how a protein called PARP-1 binds to genes and regulates their expression across the human genome. Knowing where PARP-1 is located and how it works may allow scientists to target this protein while battling common human diseases.

"This finding was unexpected -- especially since it entails a broad distribution of PARP-1 across the human genome and a strong correlation of the protein binding with genes being turned on," said W. Lee Kraus, Cornell associate professor in molecular biology and the corresponding author in the published study. Kraus has a dual appointment at Cornell's Weill Medical College in New York City. "Our research won't necessarily find cures for human diseases, but it provides molecular insight into the regulation of gene expression that will gives us clues where to look next."

Kraus explains that PARP-1 and another genome-binding protein called histone H1 compete for binding to gene "promoters" (the on-off switches for genes) and, as such, act as part of a control panel for the human genome. H1 puts genes in an "off" position and PARP-1 turns them "on." The new study, said Kraus, shows that for a surprising number genes, the PARP-1 protein is present and histone H1 is not, helping to keep those genes turned on.

When human cells are exposed to physiological signals, such as hormones, or to stress signals, such as metabolic shock or DNA damage caused by agents like ultra-violet (UV) light, the cells take action. One of the cellular responses is the production of NAD (nicotinamide adenine dinucleotide), a metabolic communication signal. NAD promotes the removal of PARP from the genome and alters PARP-1's ability to keep genes on, the scientists have found.

Knowing where this component of the genome's control panel -- the PARP-1 protein -- is located, scientists can better understand the effects of synthetic chemical inhibitors of PARP-1 activity, which are being explored for the treatment of human diseases including stroke, heart disease and cancer. Thus, conceivably, when a patient is having stroke, it may one day be possible to use PARP-1 inhibitors as part of stroke therapy, or one day play a role in targeting cancer, says Kraus.

"Think of PARP-1 as a key regulator of gene expression in response to normal signals and harmful stresses," said Kraus. "If you could control most of the traffic lights in a city's street grid with one hand, this is analogous to controlling gene expression across the genome with PARP-1. Under really adverse conditions, you can set all the lights to stop."

The article, "Reciprocal Binding of PARP-1 and Histone H1 at Promoters Specifies Transciptional Outcomes," was authored by Raga Krishnakumar (co first-author), a graduate student in molecular biology and Matthew J. Gamble (co first-author), a post doctoral researcher at Cornell; and Kristine M. Frizzell, Jhoanna G. Berrocal and Miltiadis Kininis, all Cornell graduate students in molecular biology and genetics. Kraus is the corresponding author. It is published Feb.8, 2008 in the journal Science.The National Institutes of Health funded the research.


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The above post is reprinted from materials provided by Cornell University. Note: Materials may be edited for content and length.


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Cornell University. "How One Protein Binds To Genes And Regulates Human Genome." ScienceDaily. ScienceDaily, 11 February 2008. <www.sciencedaily.com/releases/2008/02/080207140851.htm>.
Cornell University. (2008, February 11). How One Protein Binds To Genes And Regulates Human Genome. ScienceDaily. Retrieved July 5, 2015 from www.sciencedaily.com/releases/2008/02/080207140851.htm
Cornell University. "How One Protein Binds To Genes And Regulates Human Genome." ScienceDaily. www.sciencedaily.com/releases/2008/02/080207140851.htm (accessed July 5, 2015).

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