DISCOVERING THE FIRST STEPS IN TRANSCRIPTION-COUPLED REPAIR
10 July 2006 - DOE/Lawrence Berkeley National Lab

During gene transcription a molecular machine called RNA polymerase II opens a "transcription bubble" in DNA, reads the genetic information, and copies it into RNA. Most of the bubble is inside the RNAPII (the overlying "clamp module" is translucent in this depiction). If the RNAPII stalls during transcription, the transcription-coupled repair process must gain access to the transcription bubble.

If a blockage occurs when genetic information from a cell's DNA is being transcribed into RNA, an activity vital to the synthesis of proteins, the transcription-coupled repair process detects the obstruction and repairs the damage. But when TCR itself fails, the results can be lethal to cells and to the organism. In humans, failure of transcription-coupled repair is the cause of Cockayne Syndrome, an extreme form of accelerated aging that is inevitably fatal early in life.

Cooper and her colleagues illuminated, for the first time, the roles played by two important proteins in recognizing blockages in transcription and in initiating an efficient method of repair; their results suggested a previously unsuspected mechanism for the repair process.

The team, whose members hold positions at Berkeley Lab, the University of California at Berkeley, the Howard Hughes Medical Institute, the Skaggs Institute for Chemical Biology, and the Scripps Research Institute, includes Altaf Sarker, Susan Tsutakawa, Seth Kostek, Cliff Ng, David Shin, Marian Peris, Eric Campeau, John Tainer, and Eva Nogales, in addition to Cooper.

DNA is constantly under attack from sources inside and outside the body, including sunlight, ionizing radiation, other environmental carcinogens, and free radicals from the cellular metabolism. DNA damage ranges from one or a few altered nucleotides in a single strand of the double helix, to breaks in one or both strands and crosslinks between the two strands. To prevent accumulation of mutations and the production of altered proteins, cells deploy an arsenal of repair mechanisms to excise and replace defective nucleotides, reconnect broken strands, and patch up other kinds of damage.

Transcription-coupled repair is unique: it targets repair to genes that are actively being transcribed into messenger RNA. TCR was discovered about 20 years ago as a result of comparing the properties of cells from patients with Cockayne Syndrome versus those with xeroderma pigmentosum, two different hereditary diseases with a common feature: both entail extreme sensitivity to sunlight. However, in XP there is loss of ability to repair damage to DNA caused by ultraviolet radiation throughout the genome, whereas in CS the global repair mechanism is intact but transcription-coupled repair is defective. Thus active genes cannot be repaired preferentially.

In XP patients, exposure to sunlight typically causes hyper-pigmented skin that is dry and parchment-like, and is followed by multiple skin cancers. If carefully shielded from ultraviolet light, for example by window filters and protective clothing, many XP sufferers can lead seemingly normal lives. XP results from mutations in any one of seven genes, labeled XPA through XPG, which are involved in the well-understood DNA repair mechanism called nucleotide-excision repair.

In contrast, Cockayne Syndrome is marked not by skin cancer but by severe physical and mental retardation, victims have an unusually small brain and fail to grow and develop normally after birth; pronounced wasting usually begins in the first year of life. As they grow older, CS sufferers look increasingly aged, with faces marked by sunken eyes. Average life expectancy is only 12 years and few survive their teens. Cockayne Syndrome usually results from mutations in one of two genes, CSA or CSB, although mutations in three XP-associated genes, XPB, XPD, and XPG, can also cause clinical CS.

http://www.lbl.gov

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