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Scientists crack the code for DNA organisation in nucleus

By Wai Lang Chu, 24-Jul-2006

Related topics: Materials & Formulation

The discovery of a genetic code for DNA organisation within a cell's nucleus has significant implications in future drug discovery processes as cracking the genetic code that determines nucleosome location on the DNA strand will aid identification of drug targets.

Pharmaceutical companies are targeting DNA for different therapies, and they need to identify DNA or small molecules that selectively bind to DNA to turn on or off the gene expression related to a particular disease. By identifying this specific sequence, not only can drugs be made more effective, it might also be possible to predict a patient's response to a particular type of drug therapy.

At the Weizmann Institute of Science in Rehovot, Israel, researchers proved that DNA sequence also encodes "zoning" information on where to place nucleosomes.

They characterised this code and then, using the DNA sequence alone, were able to accurately predict a large number of nucleosome positions in yeast cells.

The researchers examined around 200 different nucleosome sites on the DNA and asking whether their sequences have something in common. Mathematical analysis revealed similarities between the nucleosome-bound sequences and eventually uncovered a specific "code word."

This "code word" consists of a periodic signal that appears every 10 bases on the sequence. The regular repetition of this signal helps the DNA segment to bend sharply into the spherical shape required to form a nucleosome.

To identify this nucleosome positioning code, the research team used probabilistic models to characterise the sequences bound by nucleosomes, and they then developed a computer algorithm to predict the encoded organisation of nucleosomes along an entire chromosome.

This latest discovery bodes well for gene expression control exhibited by DNA-binding drugs, which has become of great interest in molecular biology and biotechnology.

The ability of some drugs to switch on or off the gene expression brings the possibility to develop treatments for genetic diseases, infection by antibiotic-resistant bacteria, and especially cancer, which is typically accompanied or caused by mutations in the DNA and the way it organises into chromosomes.

The analysis of the DNA sequence-dependent conformational energy gives hints for the design of DNA-binding drugs that modify the DNA conformational state.

Dr. Eran Segal and research student Yair Field of the Computer Science and Applied Mathematics Department at the Weizmann Institute of Science said that since the proteins that form the core of the nucleosome are among the most evolutionarily conserved in nature, the scientists believe the genetic code they identified should also be conserved in many organisms, including humans.

Such mutational processes may be influenced by the relative accessibility of the DNA to various proteins and by the organisation of the DNA in the cell nucleus.

Therefore, the scientists believe that the nucleosome positioning code they discovered may aid scientists in the future in understanding the mechanisms underlying many diseases.

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