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Histones (round) with DNA double helix

A strand of DNA winds around several histone proteins, including H2AX (in red). University research has shown that H2AX has the peculiar ability to both repair and destroy DNA molecules.

One protein's double life

Like a molecular Dr. Jekyll and Mr. Hyde, a common protein can either enhance or destroy the DNA in its care

By Deane Morrison

July 18, 2006

Like the fictional Dr. Jekyll, a protein that normally repairs damaged DNA molecules can, when modified, chop that very DNA to bits in a decidedly Mr. Hyde-like manner. The discovery, which comes from the laboratories of the University's Hormel Institute in Austin, Minn., is a step toward understanding the process by which some cells kill themselves. The self-killing of cells is termed apoptosis, and its purposes include not only culling damaged cells but shaping an embryo by getting rid of webbing tissue between fingers and toes. By contributing to the understanding of how apoptosis works, the researchers, led by Hormel Institute Director Zigang Dong, hope someday to see the process used to kill cancer cells or other unwanted tissue. Writing in the July 7 issue of Molecular Cell, the team described the players in this cellular drama and the biochemical detective work that revealed how mouse skin cells respond to damage from ultraviolet light. The main character, the "Jekyll" protein, belongs to a class of proteins called histones, which act like spools for the "thread" of DNA molecules, keeping it organized. DNA molecules loop around the regularly spaced histones, which not only support the DNA, but play various roles in managing its functions. Without histones, DNA molecules would float around in the cell nucleus like a mess of overlong spaghetti. "In the past, people thought histones were just for packaging DNA," said Dong, who studied a histone named H2AX. "[Now] people believe they play a role in DNA repair. But we find that if DNA can't be repaired, the cell undergoes apoptosis. The histone H2AX is probably important for both apoptosis and DNA repair." The other major character in cell self-destruction is an enzyme known as JNK, which comes in different forms. Dong and his colleagues report that after they had exposed mouse skin cells to damaging amounts of ultraviolet light, a certain form of JNK initiates two cellular processes, both of which must be set in motion before DNA can be destroyed. In one process, it activates H2AX, turning it from Jekyll to Hyde. In the other process, it activates an enzyme designed to chop up DNA. When the active histone and the active enzyme combine in a cell nucleus, they join forces and start slashing DNA to bits. Dong and his colleagues are the first to show that activation of H2AX is necessary for apoptosis to occur by means of the DNA-chopping enzyme. But the work raises as many questions as it answers. For one thing, says Dong, no one knows how a cell decides whether damage to its DNA merits repair or apoptosis. Also, the various forms of the JNK enzyme present an enigma. In previous work, Dong and his colleagues found that a different form of JNK was associated with skin tumor growth. It could be, he said, that both forms of JNK evolved from a common enzyme ancestor and that small genetic changes pushed one form toward tumor growth and the other toward tumor suppression.