Disrobing chromosomal DNA

In higher organisms the genetic material in the cell nucleus is coiled around protein complexes like spools of thread. LMU researchers now show how the spools are displaced to allow the information in the DNA sequence to be read out.

14-12-2012 — /europawire.eu/ — In higher organisms, the genetic material is stored in the cell nucleus in a highly compact form. The linear DNA molecule that forms each chromosome is wrapped around particles made of proteins called histones, rather like a thread wound on a spindle. A length of DNA equivalent to 200 nucleotide base-pairs (the “rungs” of the double helix that encode the genetic information) fits around each spool, giving rise to a so-called nucleosome.Packaging into nucleosomes permits the long fibers of chromosomal DNA to fit into the nucleus and helps to protect them from breakage. However, nucleosome-associated DNA sequences cannot be transcribed and used to direct protein synthesis because they are inaccessible to the enzymes responsible for read-out of the genetic information. The histone proteins make dozens of contacts with the DNA wrapped around them, so that each nucleosome is essentially fixed in place.

Sliding the spools along the DNA
Fortunately, there are specialized enzymes that are capable of loosening these contacts, enabling the DNA to be moved relative to the nucleosome. One of the most important of these “nucleosome remodeling enzymes” is called ISWI. ISWI is known to catalyze the mobilization process by coupling the release of chemical energy to the sliding of nucleosomes along the DNA, but how this feat is accomplished has been unclear.

One popular model suggests that the process requires cooperation between two domains of the ISWI enzyme, with the ATPase domain supplying the energy for translocation and a second domain, called the HSS domain, acting to pull flanking “linker” DNA into the nucleosome. Together with their coworkers, the LMU researchers Dr. Felix Müller-Planitz and Professor Peter Becker have now shown that this idea is incorrect.

An autonomously active module
“In the fruitfly Drosophila melanogaster, we have shown that the ATPase module of ISWI participates in all aspects of nucleosome remodeling,” says Müller-Planitz. “The ATPase domain can bind autonomously to nucleosomes, and the interaction is associated with ATP hydrolysis.” The energy released is used to modify nucleosome structure in such a way that the protein particle can slide along the DNA molecule.

“Nevertheless, the HSS domain also has an important part to play,” says Becker, “as it increases the affinity and specificity of the enzyme for the nucleosomes.” In humans, the enzymes Snf2L and Snf2H are functionally equivalent to ISWI. Although it is not known whether they are of clinical relevance, other closely related nucleosome remodelers are known to be involved in the development of some forms of cancer.” (Nature Structural & Molecular Biology, 2.12.2012) suwe

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