Science and Cellular Stresses

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p53 tumor suppressor Protein Databank

The holiday season can be stressful with its just-missed parking spots and perfectly horrible holiday sweaters. And spending time bonding with family and friends can be a great way to relieve those stresses (while perhaps causing others!).

In a sense, cells studied by the Office of Science's Brookhaven National Laboratory (BNL) deal with the stresses in similar fashion. They get stressed from environmental harms like chemicals and radiation, which can damage their DNA. DNA is not simply the stuff of inheritance (an individual's entire set of DNA is called their genome), it is also a sort of instruction manual, which cells use make essential machines known as proteins.

Even low doses of radiation can damage DNA. And while cells have ways to repair that damage (more on that below), it can eventually build up and lead to various forms of cancer. The Office of Science has a history of studying radioactive materials, and strives to advance understanding of radiation's effects on the human genome—the work at BNL was one aspect of this effort.

Specifically, a team of BNL researchers led by Krassimira Botcheva looked at the bonding places for p53, a tumor-suppressor protein. As its name implies, p53 prevents tumors from forming, but it doesn't prevent damage to DNA from being done. Rather, p53 affects how the cell responds to the damage, whether by turning on a repair effort, stopping the cell from dividing or even telling the cell to self-destruct, to stop the damage from multiplying any further (uncontrolled cell division leads to tumors).

P53 does so by binding with DNA—it literally attaches at different points—and then by turning on different sets of genes, ensures building of proper proteins needed for the cells at time of stress. At least that's how it's supposed to work.

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Krassimira BotchevaBrookhaven National Laboratory

Krassimira Botcheva

BNL scientists produced the first high-resolution map of p53 binding sites in healthy human cells, and contrasted it with p53 binding sites for cancerous cells. They found two key differences. First, healthy cells have p53 binding sites near the start site for genes that affect processes like DNA repair, stress response and cell survival, while cancerous cells have p53 binding sites far from genes.

Second, BNL scientists discovered that p53 binding sites in healthy cells tend to be in places—called CpG islands—and that is exciting news because these islands are special places in the human genome with important functions—they regulate the way genes are expressed. In healthy cells these islands have lesser amounts of a special chemical tag known as a methyl group (which typically serves as a "stop" button for genes, and thus the making of their proteins). This is a fascinating finding because it may explain why in cancer cells p53 is away from genes and CpG islands as they receive more of those methyl tags during tumor development.

It's not yet clear how those changes make such a stark difference between sickness and health. But it does provide a framework for getting at the problem further. So while it won't relieve the holiday stresses, the work at BNL and the Office of Science may offer new hope in the New Year, which might be a bit comforting while staring down the neck of yet another perfectly horrible holiday sweater.

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Charles Rousseaux is a Senior Writer in the Office of Science.