[ RadSafe ] News Release: Mutant mouse enzyme able to help protect DNA from (radiation?) damage.

John Jacobus crispy_bird at yahoo.com
Mon Aug 14 08:20:28 CDT 2006

U.S. Department of Health and Human Services NATIONAL
Institute (NCI) http://www.cancer.gov/

EMBARGOED FOR RELEASE: Sunday, August 13, 2006; 1:00
p.m. ET 

CONTACT: NCI Media Relations Branch, 301-496-6641,
ncipressofficers at mail.nih.gov 


Research has shown that when DNA damage occurs, a key
enzyme -- called ataxia telangiectasia mutated
protein, or ATM -- becomes activated. A new study in
mice shows that this enzyme continues to be activated
and function normally, even without a chemical
modification previously thought to be necessary. This
study, which was conducted by scientists at the
National Cancer Institute (NCI) and the National
Institute on Aging (NIA), both parts of the National
Institutes of Health, appears online August 13, 2006,
in the journal "Nature"*.

"Although enzyme mechanisms may differ between humans
and mice, gaining a better understanding of DNA damage
repair might someday allow us to specifically alter
ATM in cancer cells. These alterations could make
tumors more sensitive to DNA damage and cell death
radiation therapy for cancer," said senior author
André Nussenzweig, Ph.D., senior investigator in NCI's
Experimental Immunology Branch.

ATM is a protein that functions to maintain the
stability of DNA. It controls the activity of many
proteins in a cell by transferring phosphate chemical
groups to these proteins. The addition of phosphate
groups is a common mechanism used by cells to turn
enzymes on and off.

Radiation and other factors can create double-stranded
breaks in DNA, and evidence suggests that ATM becomes
activated in response to this DNA damage. ATM's
activation was believed to involve a process called
autophosphorylation, in which the enzyme would add a
phosphate group to itself and then be released from an
inactive state. Subsequently, activated ATM then
migrates to sites of DNA damage and phosphorylates
other proteins that are necessary for halting the cell
cycle and repairing DNA damage.

The cell cycle is a carefully regulated process by
which cells proliferate. During the cell cycle, a cell
grows and divides to produce two new cells, and then
the process starts all over again. Bringing the cell
cycle to a standstill after DNA damage occurs allows
time for the cell's machinery to fix the errors before
abnormal cells are generated. If the damage cannot be
accurately fixed, the cell may commit cellular suicide
rather than lose control of growth.

Appropriate cell cycle regulation by ATM and other
proteins is necessary to prevent abnormal cell growth,
which can lead to cancer. In humans, individuals who
inherit a mutation in the gene encoding ATM may
develop ataxia-telangiectasia, a rare degenerative
disease that causes loss of muscle control, a weakened
immune system, and an increased risk of cancer.

Mice engineered to lack the ATM gene are also
defective in growth and are predisposed to cancer.
Mouse and human cells with non-functional ATM are also
more sensitive to radiation. Previous studies
suggested that autophosphorylation of the ATM protein
is necessary for normal function and control of cell
proliferation**. The symptoms that result from a
missing ATM gene can be alleviated by providing the
mice with a new copy of the gene.

The research reported in "Nature", led by Manuela
Pellegrini, Ph.D., and Arkady Celeste, Ph.D., of NCI's
Experimental Immunology Branch, shows that addition of
a mutant version of the ATM protein (Atm-S1987A) that
is unable to autophosphorylate can restore normal
function to mice lacking ATM. Mice with the Atm-S1987A
mutant protein appear normal and do not have the
defects that are observed in mice without ATM.

The researchers attribute the rescue of ATM-deficient
mice to the ability of the Atm-S1987A mutant protein
to function normally without autophosphorylation. Even
when immune cells from Atm-S1987A-rescued mice are
treated with radiation, several signs of normal cell
cycle inhibition were observed, including decreased
rate of DNA synthesis and decreased cell
proliferation. This mutant ATM protein also migrated
to the site of DNA breaks and phosphorylated other
proteins appropriately. None of these indicators of
regular function can be detected in immune cells from
mice lacking ATM. Therefore, the mutant Atm-S1987A
protein exhibits normal phosphorylation activity and
is sufficient to trigger an efficient response to

Since autophosphorylation appears to be nonessential
for ATM activation and function, the purpose of this
modification is unclear. "Autophosphorylation of ATM
may just be accidental, or there may be additional
sites of autophosphorylation that compensate"
speculated Nussenzweig. "Once ATM is recruited to the
double-stranded DNA break, lots of other proteins also
relocate to the same site for phosphorylation. The
high concentration of enzyme activity might result in
unintended autophosphorylation at the site we studied
or other sites." The NIH researchers next will try to
abolish all ATM autophosphorylation activity in order
to pinpoint exactly which phosphate groups might be
necessary and which are dispensable in triggering ATM
regulation of the cell cycle after radiation damage.

According to acting NCI Director John Niederhuber,
M.D., "Making tumors easier to eradicate at lower
doses of radiation, while avoiding significant harm to
healthy surrounding tissue, would be a significant
step forward in this vital area of research. What we
learn today in mice can hopefully be applied to humans
in the near future."

To learn more about Dr. Nussenzweig's research, go to:

For more information about cancer, please visit the
NCI Web site at http://www.cancer.gov, or call NCI's
Cancer Information Service at 1-800-4-CANCER

The National Institutes of Health (NIH) -- "The
Nation's Medical Research Agency" -- includes 27
Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the
primary federal agency for conducting and supporting
basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures
for both common and rare diseases. For more
information about NIH and its programs, visit

* Pellegrini M, Celeste A, Difilippantonio S, Guo R,
Wang W, Feigenbaum L, Nussenzweig A.
Autophosphorylation at Serine 1987 is dispensable for
murine Atm activation "in vivo". "Nature". Online
August 13, 2006.

** Bakkenist CJ and Kastan MB. DNA damage activates
ATM through intermolecular autophosphorylation and
dimer dissociation. "Nature". 2003; 421:499-506.
This NIH News Release is available online at:

>From an article about physicians doing clinical studies: 

"It was just before an early morning meeting, and I was really trying to get to the bagels, but I couldn't help overhearing a conversation between one of my statistical colleagues and a surgeon.

Statistician: "Oh, so you have already calculated the P value?"

Surgeon: "Yes, I used multinomial logistic regression."

Statistician: "Really? How did you come up with that?"

Surgeon: "Well, I tried each analysis on the SPSS drop-down menus, and that was the one that gave the smallest P value"."

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

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