PHILADELPHIA - A study published in the October issue of
Nature Genetics demonstrates that loss of the
tumor-suppressor protein p53, coupled with elimination of the
DNA-maintenance protein ATR, severely disrupts tissue maintenance
in mice. As a result, tissues deteriorate rapidly, which is
generally fatal in these animals. In addition, the study provides
supportive evidence for the use of inhibitors of ATR in cancer
therapy.
Essentially, says senior author Eric Brown, PhD, Assistant
Professor of Cancer Biology at the University of Pennsylvania
School of Medicine, the findings highlight the fact that day-to-day
maintenance required 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. It's
also about housekeeping, the clearing away of damaged cells.
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 DNA maintenance 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," explains Brown.
"An analogy to our findings is what happens to trees during the
changing seasons," says Brown. "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 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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