THE DNA REPAIRMAN
Investigating the mechanisms of deficient genetic repair

Deoxyribonucleic Acid. The long, complex name of the easier-to-say DNA should give us an indication of the complexity of the DNA structure itself. Like most things, DNA, the genetic coding of life, interacts with internal and external factors, whether it's a naturally-produced chemical in our cells or radiation in our environment. Damage can sometimes result from this interaction and, if not corrected, can lead to mutations and disease.
In an effort to seek out the many factors of DNA repair, LSU researcher Shisheng Li has been investigating the mechanisms of different DNA repair pathways since he became interested in DNA repair research while working on his Ph.D. at the University of Wales in the United Kingdom.

"When DNA has to repair itself, many genes get involved," says Li, an assistant professor in the LSU School of Veterinary Medicine's Department of Comparative Biomedical Sciences. "The mechanisms of DNA repair are quite complicated in eukaryotic cells, those cells that have a nucleus and specialized organelles."

Li focuses on a specific pathway of DNA repair for his research: transcription-coupled repair. Transcription is the process of copying information from the transcribed strand of DNA into messenger RNA (mRNA). The mRNA then carries this information to the cytoplasm, a semi-fluid substance that makes up a large part of the cell, where it serves as a blueprint for the manufacture of a specific protein. Proteins are essential to the structure, function, and regulation of the body's cells, tissues, and organs.

During the process of transcription, the DNA strand can sometimes sustain damage, which can result in a DNA lesion. DNA lesions in the transcribed strand are usually repaired considerably faster than in the non-transcribed strand via a transcription-repair coupling mechanism that is not yet well understood. A DNA lesion on the transcribed strand can block transcription machinery. If the blockage is not resolved through repair in a timely manner, cells could undergo apoptosis, the process of programmed cell death. Increased cell loss is thought to promote accelerated aging.

In humans, when an abnormally high level of cell loss occurs, an entire host of diseases and conditions can develop, in addition to cancer. One such disease, Cockayne's Syndrome, is a condition characterized by postnatal growth failure, progressive neurological dysfunction and premature aging. Patients with Cockayne's Syndrome typically do not live beyond their teenage years.
These diseases are caused by a defiency in the transcription-coupled repair process, which involves two subpathways mediated by RPB9 and RAD26, respectively. Thanks to a grant from the National Institutes of Health, Li is investigating the possible links between the deficiency in the two subpathways of transcription-coupled repair and Cockayne's Syndrome, as well as UV Sensitive Syndrome; Trichothio Distrophy; and Cerebrooculofacioskeletal Syndrome, a genetic disorder of the brain and spinal cord that begins before birth.

"By better understanding the mechanisms of transcription-coupled repair, we may be able to correct the repair deficiency in patients and allow them to live longer and healthier lives," says Li.

Li's research could also pave the way to developing tools that could find methods to accelerate even the death of cancerous or defective cells, if a target for blocking transcription-coupled repair in these cells can be identified. In theory, doctors could use these same mechanisms to treat or cure certain human diseases.

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LSU Department of Comparative Biomedical Sciences

from Spring 2005