NIH funds scientists’ work to unravel cell repair

 

 

PULLMAN, Wash. – Each moment, every cell in your body is being assaulted and – fortunately – fixed, thanks to the crews of handymen enzymes that travel up and down your DNA strands. Considering that you wouldn’t survive without these built-in repair systems, it’s reassuring to know that two Washington State University scientists, awarded a $1.6 million grant from the National Institutes of Health, have made it their mission to understand how the mechanisms work and why, sometimes, they fail.

 

The discoverers of the DNA structure, James Watson, left, and Francis Crick, with their model of a DNA molecule. (A. Barrington Brown/Photo Researchers, Inc.)

Almost six decades ago, a published paper with fewer than 1,000 words launched a scientific revolution when Francis Crick and James Watson revealed the twisted-ladder structure of DNA in the journal Nature. They had discovered a Rosetta stone of biology – the chemical basis of life. Fifty-eight years later, the revolution is still booming inside labs of WSU’s School of Molecular Biosciences.

There, molecular biologist and Regents Professor Michael Smerdon oversees research in DNA repair. In a project the NIH began funding 30 years ago, he is among the first scientists to analyze how the packaging of DNA in each cell contributes to the mending process.

 

His work has been groundbreaking, said Samuel Wilson of the institute’s environmental health sciences division. So impressive, in fact, that Smerdon is among the division’s top grant recipients.

 

“For decades, Smerdon has been a key figure – worldwide – in the research of chromatin structure (how DNA is packaged inside each cell) and its role in DNA repair,” said Wilson from his office near Durham, N.C.

Which is why the federal agency recently awarded Smerdon yet another grant to continue his work. Except this time it includes WSU colleague John Wyrick, a molecular biologist who hails from a family so remarkably science-minded that members were featured in a Spokesman Review article in 2003.

Smerdon and Wyrick supervise laboratories one floor apart where a handful of graduate and post-doctoral students with energy in their eyes probe deep within cells to examine how DNA repair systems work. If the team can nail this down, one day their findings could lead to preventing cancer and other diseases, as well as create better drugs to destroy them.

 

“The significance of this kind of DNA research is huge as we focus on improving human health and preventing disease,” said Wilson.

Enzymes constantly remove and repair damage to DNA.

Inside Smerdon’s office stands a shiny red, blue and white sculpture of DNA’s famed double helix – a far cry from the cardboard cutouts, colored beads and wire that Crick and Watson assembled for their model in 1953. Using his fingers, Smerdon uncoils the spiral staircase into two strands, or columns.

 

At any given time, “repair enzymes are moving along DNA strands in your body’s cells, searching for damage and correcting it,” he explained.

 

A good thing, too, since the 30 trillion cells that make up the human body are constantly under assault, not only by agents such as chemicals and ultraviolet light, but also normal wear and tear, he said.

“Just by sitting there and maintaining a body temperature of 98.6, your cells are sustaining lesions and enzymes are repairing them,” he said. “If you were being exposed to the sun or to cigarette smoke, the damage would be greater and the role of the enzymes as a frontline defense would be more significant.”

 

How these enzymes locate defects and then latch onto the spaghetti-like chromosomal coils has been the focus of Smerdon’s work. Basically, the repair system works like this: The enzymes spot the faulty area, remove it and then replace it with a fresh snip of DNA.

 

These patch-ups can’t be made, however, unless the tightly bound DNA twines do some uncoiling. Otherwise, the injured region, called an adduct, isn’t accessible to the repair enzymes.

 

Smerdon, 63, studied physics before switching to biology.

 

“I found the interplay between genes and the environment more fascinating than high-temperature superconductors,” he said.

He enters his fourth decade of DNA research with a first-time partner, the 37-year-old Wyrick, who earned an undergraduate degree at WSU in biochemistry and biophysics in 1996 before moving on to graduate work at the Massachusetts Institute for Technology.

 

The Wyrick name is well known at WSU. John, his two brothers and one sister graduated with honors in biochemistry at the university, and Smerdon was acquainted with them all. Eventually, John Wyrick returned to WSU to teach, and “I recruited a scientific star as my research partner,” said Smerdon.

 

“Doing DNA studies together, we go at it from different perspectives, largely because of our backgrounds and training,” he said. “The two of us are stronger than the sum of our parts.”

 

While Smerdon can talk a blue streak about their research – pointing his finger and exclaiming, “Yes! You’ve got it!” each time this writer appears to grasp his explanations about nucleosomes and high–order chromatin structure – Wyrick is concise, referring matter-of-factly to computer-generated illustrations to help get his point across.

When someone gets a cancer diagnosis, the nagging question is, “Why me?” For Wyrick, it’s “What went wrong with the DNA, and when?”

“If a cell’s repair system can’t correct damage to the DNA, it can lead to permanent mutations that turn cancerous later,” he said.

 

Illustration courtesy of Michael Smerdon.

On a shelf in Smerdon’s office is a framed illustration based on a sketch he scribbled on a napkin in 1980, back when he began his research at WSU. Titled “DNA Repair Shop,” it depicts two handymen in overalls repairing a partially unwound staircase of DNA, cutting out damage with a saw and inserting new material with a hammer and nails.

It is a simple rendering of a complex and clever system, not unlike the early illustrations of Watson and Crick’s double helix that depicted the blueprint of life.

Perhaps, in the second 50 years of the double helix’s discovery, the Smerdon-Wyrick collaboration will yield discoveries that reveal just what kinds of tools those handymen enzymes carry and what signals the DNA to unwind when they arrive.

“My hope is that our teamwork will one day lead to targeted therapies that relieve people from the grip of cancer and other diseases,” said Smerdon.