Cell, Heal Thyself: New Systems Biology Model Reveals How Cells Repair DNA Damage
|UCSD bioengineering professor Trey Ideker explains in this video how an understanding of DNA repair could help in the development of new strategies to fight many diseases. Length: 3:05.|
“Response to DNA damage is a basic physiological process that is important to coping with environmental toxins and a number of congenital diseases,” said Ideker, the senior author of the paper. “Over the past several decades, scientists have discovered many parts of the DNA-damage-repair machinery, but what has been missing until now is a ‘systems biology’ approach that explains how all the parts function together to enable a cell to repair its DNA while under routine assault.”
|Researchers exposed cells to a powerful mutagen and then measured how they responded to repair the damage.|
“It’s almost as if cells have something akin to a computer program that becomes activated by DNA damage, and that program enables the cells to respond very quickly,” said Mak. “And this program is easily recognizable as operating in everything from yeasts to humans and mice to fruit flies.”
Researchers have previously identified hundreds of genes involved in repairing MMS damage. However, they have been mystified by another group of genes whose expression is sharply affected by DNA damage, but which appear to play no role in repairing the damage itself.
|A team of researchers led by UCSD bioengineering professor Trey Ideker used a "systems biology" approach to uncover a detailed model of how eukaryotic cells respond to DNA damage.|
The team discovered that part of the interaction network was involved, as expected, in repairing damaged DNA. However, they were surprised to find that a much larger part of the network is involved in modulating the expression of genes not directly related to DNA repair, such as genes involved in cell growth and division, protein degradation, responses to stress, and other metabolic functions. Ideker and others have theorized that when a cell’s DNA is damaged, the cell may be programmed to also stop dividing and perform a variety of housekeeping chores while it repairs its DNA. If true, the model may demystify the long-standing question of why DNA damage influences the expression of hundreds of genes not involved in the actual repair process.
“What we quickly realized is that we had uncovered not just a model of DNA repair, but a blueprint of how the initial event of DNA damage is transmitted by these transcription factors to repair processes and all the other important functions of the cell,” said Ideker. “With this model now in hand, we’d like to take a much closer look at the cell’s response to environmental toxins. We’d like to understand what goes wrong in certain congenital diseases involving DNA repair, and we’d also like to understand how the model plays a role in various cancers.”
"This research sheds light on the complexity of DNA repair, and offers an example of how the cellular process stimulates other pathways," said David Schwartz, director of the National Institute of Environmental Health Sciences (NIEHS), one of the agencies which funded the study, agreed that the new findings could have practical benefits. "This new knowledge has great potential for the development of new therapeutic agents to combat a broad spectrum of diseases, including cancer, neurodegenerative diseases, and premature aging."
Other researchers involved in the project include: Jean-Bosco Tagne and Owen Ozier, Whitehead Institute for Biomedical Research, Cambridge, MA; Thomas J. Begley, University of Albany-SUNY, Rensselaer, NY; and Leona Samson, professor of toxicology and biomedical engineering, MIT, Cambridge, MA.
Jacobs School of Engineering