Study finds direction of enzymes affects DNA repair

DNA repair enzymes do a much better job of repairing damaged genes if they are facing in one direction instead of the other. This and other details of how DNA repair is performed are reported in the online version of the journal Proceedings of the National Academy of Sciences by researchers at Washington State University and the National Institute of Environmental Health Sciences.

According to the new study, the repair enzymes “distinguish” between various positions and may be two to three times as effective, depending on whether the damage to be repaired is facing “toward” or “away from” the nucleosome, the protein-DNA complex that folds the very long DNA strands into the tiny nucleus of a cell and gives enzymes access to the DNA for repair and for replication when the cell divides.

Washington State’s senior author, Michael J. Smerdon, explained, “Like a child’s face, our DNA gets smudged up all the time by environmental and bodily chemicals. Our work provides additional details about how our cells work to clean the DNA up – to correct our heredity molecule, the DNA helix that is within each living cell.” The explosion of research on DNA repair dates back less than a decade, to the demonstration that some colon cancer and xeroderma pigmentosum are linked to faulty DNA repair. Xeroderma pigmentosum is a rare condition in which the skin is extremely sensitive to the sun and other ultraviolet light, resulting in extreme freckling and aging.

A key element of the report is the finding of a strong “down-regulation” of one of the repair enzymes, DNA polymerase ß (pol ß) in the presence of the nucleosome. This means that nucleosome formation on DNA can inhibit base excision repair of a nucleosome-sequestered DNA lesion. Such down-regulation could have huge biological implications, since repair of such DNA damage will be blocked at the pol ß step. Such a blocking of repair will ultimately lead to mutations or other genomic instability or will interrupt cell growth.

“This changes our thinking about nucleosomes and base excision repair,” Samuel Wilson, M.D., Ph.D., deputy director of NIEHS and its researcher on the project, said. “We are still just scratching the surface of the study of cellular regulation, but the potential seems clear. The findings demonstrate how close we are to the day when, if the body fails to make the right regulatory corrections, physicians may be able to step in and make them anyway. In other words, to make corrections before diseases – a cancer or Alzheimer’s, for example – can develop.”

Brian C. Beard, Ph.D., of WSU’s School of Molecular Biosciences carried out the study under the guidance of Drs. Smerdon and Wilson.

The double-coil shape of the DNA molecule which manages our heredity and directs our cells was described 50 years ago. Almost immediately, it became clear that toxic agents in the environment and in the body can produce adverse changes in the DNA. Handily, however, these alterations are generally repaired by the body’s mechanisms, much the way “spell check” repairs misspelled words on a computer. Actually, it is much more complicated than that:

In repairing some 10,000 to 20,000 DNA adducts or lesions that occur each day in each of a human’s 10 trillion cells, repair enzymes travel up and down the double helix strands of DNA until they find a damaged area. The enzymes cut out the lesion and fill the gap with fresh DNA.

All this is performed in very tight quarters. Each human cell has a strand of DNA that is almost two meters long. This is tightly coiled in the bead-like nuclerosomes and densely folded in order to fit inside the tiny nucleus of the cell.

Repairs are complicated by this compact packaging, and Dr. Smerdon has shown that repair of damage cannot proceed until the DNA is unfolded.

He said recently that understanding the repair of DNA in specific regions of the packaged structure in the cell nucleus is “crucial to understanding why certain DNA lesions are not repaired for long times in human cells. Such ’long-lived’ lesions can form mutations and ultimately lead to cancer.”

In 1978, Dr. Smerdon received a Young Environmental Scientist Award from NIEHS, which has continued to support his research. In 2002, NIEHS awarded Dr. Smerdon a ten-year $3.58 million MERIT – Method to Extend Research in Time – award to further his groundbreaking studies.

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Dr. Smerdon can be reached at smerdon@mail.wsu.edu or (509) 335-6853
Dr. Wilson can be reached at wilson5@nieh.nih.gov or (919) 541-3267
Dr. Beard can be reached at brianc@mail.wsu.edu

Additional Contact:
Tom Hawkins, (919) 541-1402