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Discovering the first steps in transcription-coupled repair

runcated form of XPG, the result is profound Cockayne Syndrome and very early death.

Through an ingenious series of biochemical experiments, Cooper and her colleagues discovered evidence that XPG and CSB must work together in recognizing stalled RNAPII. The researchers learned that these proteins spot stalled RNAPII whether or not there is damage to DNA -- suggesting that a hitch in the transcription process, not necessarily involving damage to the DNA itself, is the cause of subsequent problems.

"It appears that XPG is needed to help CSB recognize the stalled RNAPII and carry out its other functions in TCR," says Cooper. "We think that even if CSB is present, if the cell is missing XPG, the CSB won't work as effectively." This could help explain why mutations in the gene for XPG can cause Cockayne Syndrome even when the gene for CSB is normal.

Fixing the machinery

The first step in TCR is the recognition that an RNAPII is stalled. Subsequently one of several things must happen. Most theoretical models have assumed that the stalled RNAPII has to be degraded and moved out of the way so the lesion can be repaired, after which transcription of the gene must start over with a new RNAPII.

Other possibilities are that the original RNAPII is somehow made to start up again, bypassing the lesion, or that the RNAPII is made to back up, digesting some of the messenger RNA it has already made, and have another go at transcription. In these cases, the likelihood of errors in the transcribed RNA and eventually in the resulting protein is increased.

What Cooper and her colleagues found, however, was a different, unexpected path. It appears that instead of being removed, the stalled RNAPII can be left in place and remodeled by the protein machinery of transcription-couple repair, so that repairs to the DNA can proceed without the loss of the messenger RNA that has already been formed.

The researchers created artificial
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Source:DOE/Lawrence Berkeley National Laboratory


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