The Raelian Movement
for those who are not afraid of the future : http://www.rael.org
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Newly Discovered DNA Repair Mechanism
http://www.sciencedaily.com/releases/2010/10/101004112156.htm
ScienceDaily (Oct. 5, 2010) — Tucked within its double-helix
structure, DNA contains the chemical blueprint that guides all the
processes that take place within the cell and are essential for life.
Therefore, repairing damage and maintaining the integrity of its DNA
is one of the cell's highest priorities.
Researchers at Vanderbilt University, Pennsylvania State University
and the University of Pittsburgh have discovered a fundamentally new
way that DNA-repair enzymes detect and fix damage to the chemical
bases that form the letters in the genetic code. The discovery is
reported in an advanced online publication of the journal Nature on
Oct. 3.
"There is a general belief that DNA is 'rock solid' -- extremely
stable," says Brandt Eichman, associate professor of biological
sciences at Vanderbilt, who directed the project. "Actually DNA is
highly reactive."
On a good day about one million bases in the DNA in a human cell are
damaged. These lesions are caused by a combination of normal chemical
activity within the cell and exposure to radiation and toxins coming
from environmental sources including cigarette smoke, grilled foods
and industrial wastes.
"Understanding protein-DNA interactions at the atomic level is
important because it provides a clear starting point for designing
drugs that enhance or disrupt these interactions in very specific
ways," says Eichman. "So it could lead to improved treatments for a
variety of diseases, including cancer."
The newly discovered mechanism detects and repairs a common form of
DNA damage called alkylation. A number of environmental toxins and
chemotherapy drugs are alkylation agents that can attack DNA.
When a DNA base becomes alkylated, it forms a lesion that distorts the
shape of the molecule enough to prevent successful replication. If the
lesion occurs within a gene, the gene may stop functioning. To make
matters worse, there are dozens of different types of alkylated DNA
bases, each of which has a different effect on replication.
One method to repair such damage that all organisms have evolved is
called base excision repair. In BER, special enzymes known as DNA
glycosylases travel down the DNA molecule scanning for these lesions.
When they encounter one, they break the base pair bond and flip the
deformed base out of the DNA double helix. The enzyme contains a
specially shaped pocket that holds the deformed base in place while
detaching it without damaging the backbone. This leaves a gap (called
an "abasic site") in the DNA that is repaired by another set of
enzymes.
Human cells contain a single glycosylase, named AAG, that repairs
alkylated bases. It is specialized to detect and delete
"ethenoadenine" bases, which have been deformed by combining with
highly reactive, oxidized lipids in the body. However, AAG also
handles many other forms of akylation damage. Many bacteria, however,
have several types of glycosylases that handle different types of
damage.
"It's hard to figure out how glycosylases recognize different types of
alkylation damage from studying AAG since it recognizes so many," says
Eichman. "So we have been studying bacterial glycosylases to get
additional insights into the detection and repair process."
That is how they discovered the bacterial glycosylase AlkD with its
unique detection and deletion scheme. All the known glycosylases work
in basically the same fashion: They flip out the deformed base and
hold it in a special pocket while they excise it. AlkD, by contrast,
forces both the deformed base and the base it is paired with to flip
to the outside of the double helix. This appears to work because the
enzyme only operates on deformed bases that have picked up an excess
positive charge, making these bases very unstable. If left alone, the
deformed base will detach spontaneously. But AlkD speeds up the
process by about 100 times. Eichman speculates that the enzyme might
also remain at the location and attract additional repair enzymes to
the site.
AlkD has a molecular structure that is considerably different from
that of other known DNA-binding proteins or enzymes. However, its
structure may be similar to that of another class of enzymes called
DNA-dependent kinases. These are very large molecules that possess a
small active site that plays a role in regulating the cells' response
to DNA damage. AlkD uses several rod-like helical structures called
HEAT repeats to grab hold of DNA. Similar structures have been found
in the portion of DNA-dependent kinases with no known function,
raising the possibility that they play an additional, unrecognized
role in DNA repair.
The new repair mechanism may also prove to be the key to understanding
the differences in the way that the repair enzymes identify and repair
toxic and mutagenic lesions. That is important because mutagenic
lesions that the repair mechanisms miss are copied to daughter cells
and so can spread whereas the deleterious effects of toxic lesions are
limited to the original cell.
Understanding these differences could lead to more effective
chemotherapy agents, Eichman points out. These drugs are strong
alkylating agents designed to induce lesions in a cancer patient's
DNA. Because cancer cells are reproducing more rapidly than the body's
normal cells, the agent kills them preferentially. However, in
addition to toxic lesions that kill the cell, the agent also produces
lesions that cause mutations, which can lead to additional
complications. Additionally, the efficacy of these drugs is low
because they are working against the body's repair mechanisms. If it
were possible to design a chemo drug that predominantly creates toxic
lesions, however, it should be more effective and have fewer harmful
side-effects. Alternatively, if we understood how glycosylases
recognize alkylation damage, it may be possible to design a drug that
specifically inhibits repair of toxic, but not mutagenic lesions.
Vanderbilt graduate student Emily H. Rubinson, A.S. Prakasha Gowda and
Thomas E. Spratt from Pennsylvania State University College of
Medicine and Barry Gold from the University of Pittsburgh contributed
to the study, which was supported by grants from the American Cancer
Society, National Institutes of Health and U.S. Department of Energy.
Story Source:
The above story is reprinted (with editorial adaptations by
ScienceDaily staff) from materials provided by Vanderbilt University.
The original article was written by David F. Salisbury.
Journal Reference:
1. Emily H. Rubinson, A. S. Prakasha Gowda, Thomas E. Spratt, Barry
Gold, Brandt F. Eichman. An unprecedented nucleic acid capture
mechanism for excision of DNA damage. Nature, 2010; DOI:
10.1038/nature09428
------------------------------------
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
"Ethics" is simply a last-gasp attempt by deist conservatives and
orthodox dogmatics to keep humanity in ignorance and obscurantism,
through the well tried fermentation of fear, the fear of science and
new technologies.
There is nothing glorious about what our ancestors call history,
it is simply a succession of mistakes, intolerances and violations.
On the contrary, let us embrace Science and the new technologies
unfettered, for it is these which will liberate mankind from the
myth of god, and free us from our age old fears, from disease,
death and the sweat of labour.
Rael
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
-----------------------------------------------------------------
Tell your friends who love scientific news that they can
subscribe to this list !!
They can do it by sending a blank email to:
rael-science-select-subscribe@yahoogroups.com
It's free !
-----------------------------------------------------------------
To unsubscribe, send an email to:
rael-science-select-unsubscribe@yahoogroups.com
-----------------------------------------------------------------
To change your e-mail address, unsubscribe from the old address and subscribe from the new address (see above).
-----------------------------------------------------------------
Yahoo! Groups Links
<*> To visit your group on the web, go to:
http://groups.yahoo.com/group/rael-science-select/
<*> Your email settings:
Individual Email | Traditional
<*> To change settings online go to:
http://groups.yahoo.com/group/rael-science-select/join
(Yahoo! ID required)
<*> To change settings via email:
rael-science-select-digest@yahoogroups.com
rael-science-select-fullfeatured@yahoogroups.com
<*> To unsubscribe from this group, send an email to:
rael-science-select-unsubscribe@yahoogroups.com
<*> Your use of Yahoo! Groups is subject to:
http://docs.yahoo.com/info/terms/
0 comments:
Post a Comment