A scope for the cancer treatment.

Loss of Tumor-Suppressor and DNA-Maintenance Proteins

                                                             

A study reported in the recent issue of Nature Genetics demonstrates that loss of the tumor-suppressor protein p53, coupled with elimination of the DNA-maintenance protein ATR .The study provides supportive evidence for the use of inhibitors of ATR in cancer treatment. 

A research at the University of Pennsylvania School of Medicine. The findings highlight the fact that day-to-day maintenance mandatory to keep proliferative tissues like skin and intestines functional is about more than just regeneration, a stem cell-based process that forms the basis of tissue renewal.

Whereas loss of ATR causes DNA damage, the job of p53 is to monitor cells for such damage and either stimulate the early demise of such cells or prevent their replication, the housekeeping part of the equation. The findings indicate that as messy as things can become in the absence of a DNOne of the majortenance protein like ATR, failing to remove resulting damaged cells by also deleting p53, is worse. "Because the persistence of damaged cells in the absence of p53 prevents appropriate tissue renewal, these and other studies have underscored the importance not only of maintaining competent stem cells, but also of eliminating what gets in the way of regeneration.

The finding of an analog,  is what happens to trees during the changing seasons."In springtime, leaves are new and undamaged. But as the summer wears on, the effects of various influences - insects, drought, and disease - cause them to lose the pristine qualities they once had. However, the subsequent fall of these leaves presents a unique opportunity for regeneration later on, a chance 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 appears to 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. Prior studies pairing DNA-repair mutations with p53 mutations always led to a partial rescue of the DNA repair mutation. It was thought that,this happens because p53 loss helps cells with just a little DNA damage to continue to contribute to the tissue.

But the result was opposite,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.It is thought that this could be because the ATR mutation produces much more damage than most other DNA-repair defects. 

It was found that 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 particularly susceptible to ATR inhibition." Indeed, clinical trials already are underway involving an ATR partner protein called Chk1.So the study provided with the potential use of ATR/Chk1 inhibitors in cancer treatment.