The transcription factor and oncoprotein MYC is a potent driver of many human cancers and can regulate numerous biological activities that contribute to tumorigenesis. Researchers at the Institute of Biochemistry and Molecular Biology at Julius-Maximilians-Universität Würzburg report that MYC proteins form spheres that protect sensitive parts of the genome. If these MYC spheres are destroyed, cancer cells will die.
The study is published in Nature in an article titled, “Multimerization of MYC shields stalled replication forks from RNA polymerase.”
“Oncoproteins of the MYC family drive the development of numerous human tumors,” wrote the researchers. “In unperturbed cells, MYC proteins bind to nearly all active promoters and control transcription by RNA polymerase II. MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome.”
The researchers observed that when the cells in the lab are kept under stressful conditions similar to those found in fast-growing tumor cells, the MYC proteins in the cell nucleus rearrange themselves.
The hollow spheres protect sensitive sites in the genome—precisely the sites where two types of enzymes can collide: enzymes that read DNA to synthesize RNA and enzymes that duplicate DNA. Both can be thought of as two trains traveling on only one track, on DNA.
The hollow spheres thus prevent the two enzymes from colliding. The Würzburg team was able to confirm this observation in cancer cells.
“These observations revolutionize our understanding of why MYC proteins are so crucial for the growth of tumor cells,” said Martin Eilers, PhD, profressor of biochemistry at Julius-Maximilians-Universität Würzburg. The new findings also raise the question of whether drugs can be developed that specifically prevent the formation of the hollow spheres.