USC Researchers Define Role of Protein, Identify Oxygen as Cause of Chromosome Damage

[Guest guest]

Hi All,

Too bad the paper didn't suggest caloric restriction and eating high ORAC foods

as proven ways to reduce undesirable

free radical activity.

http://www.lef.org/news/aging/2002/03/12/eng-ascribe/eng-ascribe_160706_208_7826\

00020058.html

USC Researchers Define Role of Protein, Identify Oxygen as Cause of Chromosome

Damage

AScribe Newswire

University of Southern California

March 12, 2002

LOS ANGELES, March 12 (AScribe Newswire) --

Pinpointing oxygen as the cause of routine chromosome damage and defining the

role of a key protein in the repair of

that damage are the subjects of two recently published papers from the

laboratory of USC/Norris Comprehensive Cancer

Center pathologist Lieber, the Rita and Polusky Chair in Basic

Cancer Research at the Keck School of

Medicine.

The first paper was published in the March 5, 2002, issue of Current Biology;

the other is slated for the March 22 issue

of Cell, but was posted on the journal's Web site on March 1 as part of their

" immediate early publication process. "

The Cell paper, which will reportedly be on the cover of the March 22 issue,

reveals that a protein previously linked to

a devastating form of immunodeficiency plays a key role in a pathway by which

nuclear DNA is repaired-the same system,

in fact, which the immune system uses to create antibodies.

About 15 percent of the cases of human severe combined immunodeficiency syndrome

(known colloquially as the " bubble boy "

disease) are caused by the mutation of a specific gene and its protein product.

In April of 2001, a team of French

researchers tracked down that gene, and named it and its product Artemis (after

the Greek goddess for the protection of

children); they had no idea at all, however, what kind of protein it was, nor

what its function might be.

Enter Lieber and graduate student Yunmei Ma. Lieber, Ma and their colleagues

from the University of Ulm in Germany,

conclusively demonstrated that Artemis is a key protein in the repair of

double-stranded DNA breaks, a process called

NHEJ (non-homologous DNA end joining). In the NHEJ pathway, explained Lieber,

the ends of the broken DNA strands are

trimmed and rejoined to one another. " What Artemis does is trim away the damaged

parts of the DNA so that the strands

can be joined, " said Lieber.

Artemis and the NHEJ pathway are so essential, Lieber continued, that mice

lacking NHEJ usually die at birth-and those

that don't generally lack an immune system entirely and experience accelerated

aging. And, as the previous studies have

shown, humans with a defective Artemis protein also wind up without any immune

defense to speak of. That, says Lieber,

is because the immune system creates its defenses by cutting and then rejoining

bits of nuclear DNA (the rejoining

relies on NHEJ). Without Artemis, the cells can't create the antibodies

necessary to go after the myriad pathogenic

invaders we regularly encounter.

Of course, being unable to cut and splice DNA can sometimes actually be of

benefit. " What we're going to do next, " said

Ma, the paper's first author, " is try to screen for drugs that inhibit Artemis,

because this might be useful from a

cancer therapy standpoint. If we could just give a pulse of drug inhibitor for a

while, we might be able to focus the

effects of radiation therapy, for instance, by not allowing the cancer cells to

repair themselves after being hit with

the radiation. "

Still, noted Lieber, for normal cells, Artemis and the NHEJ pathway are

absolutely critical for survival. And that is

because of how exquisitely vulnerable our cells are to DNA damage in the first

place. Indeed, he said, all you have to

do is take some cells out of the organism in which they live and look at them

under a microscope, and you'll find that 5

to 10 percent of them will have at least one broken chromosome.

Normally, of course, the NHEJ pathway works to fix those breaks. But the NHEJ

pathway doesn't always function at full

capacity. Indeed, a paper published by Lieber, M.D./Ph.D. student Zarir E.

Karanjawala, and Norris Cancer Center

researcher Chih-Lin Hsieh in 1999 found that in cells where the NHEJ pathway is

disabled or missing, the number of cells

with at least one chromosome break goes shooting up to 60 percent.

What causes all this breakage? In the March 5 issue of Current Biology,

Karanjawala, Lieber, and colleagues say it's the

most ubiquitous of sources: oxygen.

Originally, said Karanjawala, they had wondered if the damage might be coming

from some environmental source, perhaps

from background radiation. But when they began to look more closely, said

Karanjawala, they found it was in the very air

we breathe. " It's coming from the oxygen, " Karanjawala explained. " We found that

if you vary the oxygen levels in which

cells are grown, the breakage levels of the chromosomes vary as well--the higher

the oxygen level, the more breakage

you'll see. "

The oxygen causes its damage, Lieber said, through oxidative free

radicals-highly reactive atoms with an unpaired

electron that can rip through our cells " like a bullet. "

" Our bodies are being riddled with these bullets every day, " explained Lieber,

" whether we like it or not. And the sorts

of double-strand DNA breaks we were looking at are hard to repair. Even if you

put the two ends together the best you

can, you usually lose a couple of nucleotides along the way. And so every time

we get an oxidative free radical hit,

which happens several times per day per cell, we lose a little info. Every time

it hits your DNA, you wind up with a

little less genetic information than you had when you started the day. "

The solution? ly, said Lieber, there may be none. " Oxygen - can't live with

it, can't live without it, " he

commented. " We need it to survive, but ultimately, it's also probably what kills

us. "

Citation: Yunmei Ma, Ulrich Pannicke, Klaus Schwarz and R. Lieber,

" Hairpin Opening and Overhand Processing by

an Artemis/DNA-Dependent Protein Kinase Complex in Nonhomologous End Joining and

V(D)J Recombination. " Cell Immediate

Early Publication, March 1, 2002, http://www.cell.com

Citation: Zarir E. Karanjawala, Niamh , R. Hinton, Chih-Lin Hsieh

and R. Lieber, " Oxygen Metabolism

Causes Chromosome Breaks and Is Associated with the Neuronal Apoptosis Observed

in DNA Double-Strand Break Repair

Mutants. " Current Biology, Vol. 12, pp. 397-402, March 5, 2002.

========================

Good health & long life,

Greg ,

http://optimalhealth.cia.com.au