Mayo Clinic researchers have shown that a molecule called Cul4 helps to deposit DNA-packaging histone proteins onto DNA, an integral step in cramming yards of genetic code into compact coils that can fit into each cell. When DNA isn’t packaged correctly, it can lead to the genomic instability characteristic of many forms of cancer.
The research is published in the Nov. 7 issue of the journal Cell. The results explain on a molecular level how Cul4 enables the handoff of histones from the proteins escorting them from their birthplace in the cell to their workplace on the DNA, where they can begin wrapping DNA up into tidy units called nucleosomes.
“We suggest that cancer cells may have evolved a mechanism to disrupt proper nucleosome assembly by altering Cul4 and other factors, which in turn could affect the stability of the genome and promote the formation of tumors,” says senior study author Zhiguo Zhang, Ph.D., a molecular biologist at Mayo Clinic.
To protect the integrity of the genome, DNA is packaged tightly, first around spools of histone to form nucleosomes, then stacked on top of each other to form chromatin and finally looped and coiled to form chromosomes. Depending on whether and how histones interact with a given genetic sequence, the DNA is either closed up tightly within this package or lies open so that the underlying genes can be read and become active. Researchers have long known that special proteins -- called histone chaperones -- escort histones around the cell, but how they finally let go of the histones to deposit them onto DNA was unclear.
Dr. Zhang wondered if Cul4, which is altered in a number of human cancers, including breast cancer, squamous cell carcinomas, adrenocortical carcinomas, and malignant mesotheliomas, might be involved. So he and his colleagues developed a series of cellular assays in yeast and in human cells to investigate the role of Cul4 in nucleosome assembly. They found that Cul4 modifies the chemical entities on the surface of the histones, weakening the interaction between them and the histone chaperones charged with their care. They noticed that the same observations held true in the yeast indicating that the role of Cul4 in nucleosome assembly and genome stability is likely conserved between yeast and human cells.
“We uncovered a novel molecular mechanism whereby Cul4 regulates nucleosome assembly,” says Dr. Zhang. “Our finding underscores the fact that proper regulation of the nucleosome assembly pathway is a key step in maintaining genome stability and epigenetic information.”