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Loss of tumor-suppressor and DNA-maintenance proteins causes tissue demise
Date:10/15/2009

ce to rejuvenate from anew without pre-existing obstacles. Similarly, by suppressing the accumulation of damaged cells in tissues, p53 permits more efficient tissue renewal when ATR is deleted."

Cells without ATR that remain uncleared may be block tissue regeneration either by effectively refusing to relinquish space to undamaged cells, or by secreting signals that halt regeneration until they have been removed.

These results came as something of a surprise, says Brown. Previous studies pairing DNA-repair mutations with p53 mutations always led to a partial rescue of the DNA repair mutation "We think this happens because p53 loss helps cells with just a little DNA damage to continue to contribute to the tissue" says Brown. So at a minimum, the team expected nothing to happen.

"But we got the opposite result: Absence of p53 did not rescue the tissue degeneration caused by ATR loss, it made it much worse. This result suggested that allowing mutant cells without ATR to persist is more harmful to tissues than eliminating them in the first place." Brown speculates that could be because the ATR mutation produces much more damage than most other DNA-repair defects.

According to Brown, their findings and those of other laboratories also reinforce the potential of a new therapeutic for cancer. That's because, among their other discoveries, the team noticed that cells missing both ATR and p53 have more DNA damage than those missing either gene alone. As a large fraction of human cancers have p53 mutations, he says, "p53-deficient tumors might be especially susceptible to ATR inhibition." Indeed, clinical trials already are underway involving an ATR partner protein called Chk1. "Our study provides supportive evidence for the potential use of ATR/Chk1 inhibitors in cancer therapy," says Brown


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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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Loss of tumor-suppressor and DNA-maintenance proteins causes tissue demise
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