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Discovering the first steps in transcription-coupled repair

utations 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 (CS) versus those with xeroderma pigmentosum (XP), 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.

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Source:DOE/Lawrence Berkeley National Laboratory


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