AW: [ RadSafe ] AW: Gasteiner Heilstollen for holiday!?

[Herren, Roy WS.]

I apologize for the length of the following article but I think that it goes to John Jacobus's statement that "biological repair is not unique to radiation".  Note in a below paragraph that the author states, "FANCD2 is then believed to work with BRCA1 protein to repair the constant DNA damage that results from excessive sunlight, radiation, exposure to carcinogenic chemicals and even from normal cell division". 

 

 

Roy Herren

Physical Science Technician

Radiation Safety Branch of the Radiology Department

Veterans Affairs Medical Center San Francisco, CA

 


Source:

Rockefeller University

 


Date:

2005-08-22


URL:

http://www.sciencedaily.com/releases/2005/08/050821230248.htm

  _____  


New Gene Associated With Fanconi Anemia 'Explains' Hallmark Chromosomal Instability


Surprising findings from just five patients has led to the first proof of how the rare disorder Fanconi anemia causes chromosomal instability. A team of international researchers, led by scientists at Rockefeller University, reports the findings in the September issue of Nature Genetics. 

The scientists found a gene mutation not previously known to be related to Fanconi anemia, and they say that BRIP1 is the first gene associated with the disease whose protein has a known function. That protein, known as BACH1, normally helps DNA unwind in order to be repaired, and if it cannot function, chromosomal damage accumulates, they say. 

"We have known for decades that patients with Fanconi anemia have chromosomes that break easily, but none of the many genes previously found to be associated with the disease explained this phenomenon. This new link to BRIP1 mutations may have revealed a central player in development of the disease," says the study's principal investigator, Arleen Auerbach, Ph.D., who directs the Laboratory of Human Genetics and Hematology at Rockefeller. Working with her were researchers from two German universities and from Memorial Sloan-Kettering Cancer Center in New York. 

"Given these new findings, we can now suggest that DNA double-strand breaks are the lesions that underlie the pathology of this disease," says Auerbach, who is internationally known for her work on the disorder and for the large Fanconi anemia registry she maintains at Rockefeller. 

Fanconi anemia (FA) is an inherited disorder characterized by developmental abnormalities, life-threatening bone-marrow failure, and predisposition to a variety of cancers. Researchers have long known that patients with the disease have chromosomes that are not readily repaired when they break; in fact, a blood test created in 1981 by Auerbach, which uses a chemical that specifically increases that damage, is now used worldwide to diagnose FA. 

Auerbach and others suspected this hallmark chromosomal instability is associated with defects in caretaker genes that help maintain the integrity of DNA. One reason for this hypothesis is that some already identified Fanconi anemia proteins accumulated in the nuclei of normal cells along with protein produced by the gene BRCA1, which is believed to help maintain DNA stability, but when mutated, is the major breast cancer susceptibility protein. 

Researchers had theorized that the underlying fault in FA lies in the seven genes that need to work together to produce a protein "complex" that activates another existing cellular protein known as FANCD2. FANCD2 is then believed to work with BRCA1 protein to repair the constant DNA damage that results from excessive sunlight, radiation, exposure to carcinogenic chemicals and even from normal cell division. 

"All of these seven Fanconi genes have to be normal -- if one isn't, then FANCD2 is not activated," says Auerbach. But she adds that no one knows what the proteins FANCD2, BRCA1 or even BRCA2 -- produced by another breast cancer susceptibility gene that has also been linked to FANCD2 -- are actually doing. 

"No one knows the precise role of any of these genes and proteins, but we believe that if BRCA1 or BRCA2, or any of the Fanconi genes that activate D2 are defective, a sequence of events is disrupted and DNA repair is blocked," she says. 

But Auerbach and her team of researchers were puzzled that about 20 patients in the 1,000-plus International Fanconi Anemia Registry (IFAR) had no mutations in any of the genes known to be associated with the disease, yet there was no question they had Fanconi anemia. "These patients had the disease, yet their FANCD2 was activated normally, and there were no problems with BRCA1 or BRCA2," she says. 

So Auerbach and her colleagues selected four families for a detailed gene analysis, based on the suspicion that there was, in each of the families, a "founder effect" -- a change in the frequency of a gene mutation that occurs when a population is descended from only a few individuals. Two of these families were Inuit (aboriginal Canadians): one had two children with Fanconi anemia and the other family had a single child with the disease. "We suspected there was a single mutation in a single gene that affected these children," Auerbach says. 

The researchers also selected two Hispanic families in which they knew the parents were first cousins, and each had an affected child. 

The researchers first applied a test that could tell them whether the offending gene was "upstream" or "downstream" from activated FANCD2 -- that is, did action of the mutant gene fall in the molecular pathway before FANCD2 was activated, or after, respectively? The answer was that the problem was located downstream from a normally functioning FANCD2. 

The researchers then mapped SNPs in the genome of those patients and families, looking for changes in which a single chemical building block in the DNA differs from the usual building block at that position. Because FA is a recessive genetic disease, an affected child needs to inherit two copies of an errant gene, each from a parent that carried a single mutation. 

They were startled to find only one suspect location in the entire genome, on chromosome 17, that was present in all four families. Further research uncovered two candidate genes within that region, and none of the patients had an abnormality in one of them. But they all had mutations in the second gene, BRIP1. 

"What was very surprisingly to us is that while all five patients were homozygous for a mutation in the gene, as expected, all had the same mutation in this gene," Auerbach says. In other words, the five patients each inherited two copies of the same mutation, one from each parent. 

When the researchers looked at the other families in their registry with no known mutations in any of the genes associated with the disease, they found six more patients with this same BRIP1 mutation, three of whom were homozygous. 

Now the story began to make sense to the researchers, since the protein, BACH1, produced by BRIP1, was known to be a DNA helicase, a class of enzymes which unwind the two strands of the DNA double helix so that DNA synthesis can take place. And they knew from the scientific literature that BACH1 interacts with BRCA1 protein. 

"This is the first gene associated with Fanconi anemia that we have a defined function for," says Auerbach. "It interacts directly with BRCA1, and is known to play a role in the repair of DNA double-strand breaks." 

BACH1 could be the link between FANCD2 and BRCA1, the researchers say. 

"It may be that DNA can't be repaired without a normally functioning BACH1," says Auerbach. "So perhaps FANCD2 activation isn't the endpoint, as had been thought, but that it has to do something downstream that can't be accomplished if BACH1 is not present." 

###

The study was funded in part by grants from the National Institutes of Health, the Joel and Joan Smillow Initiative, and Kinderkrebsklinik Duesseldorf. Contributing to the study are, from Rockefeller, first author Orna Levran, Ph.D., Rashida Henry, M.S., Kelly Milton, B.A., Sat Dev Batish, Ph.D., Sandra Barral, Ph.D., and Jurg Ott, Ph.D.; Claire Attwooll, Ph.D., and John Petrini Ph.D., from Memorial Sloan-Kettering Cancer Center; Kornelia Neveling, B.S., Reinhard Kalb, B.S., and Detlev Schindler, M.D., from the University of Wuerzburg, Germany; and Paula Rio, Ph.D., Eunike Velleuer, B.S., and Helmut Hanenberg, M.D., from Heinrich Heine University in Duesseldorf, Germany. 

  _____  

This story has been adapted from a news release issued by Rockefeller University.

 

 

 

-----Original Message-----
From: radsafe-bounces at radlab.nl [mailto:radsafe-bounces at radlab.nl] On Behalf Of John Jacobus
Sent: Monday, August 22, 2005 1:49 PM
To: Rainer.Facius at dlr.de; jimm at WPI.EDU; rad-sci-l at WPI.EDU; radsafe at radlab.nl
Subject: Re: AW: [ RadSafe ] AW: Gasteiner Heilstollen for holiday!?

 

Ranier, 

Thank you for the reply.  I am about 500 emails behind

as I was off-line for about a month.  (Actually, the

number of interesting e-mails, such as yours, are

probably less than 50.)

 

Biological repair is certainly not unique to

radiation. That is why certain toxic chemicals do not

kill at low doses or dose rates.  In our country, the

Environmental Protection Agency has threshold limit

values (TLV).  In radiation protection, we have

exposure limits, which are certainly above background

levels.  

 

I don't consider the statement that radiation "may

result from the induction of repair enzymes" to be all

that surprising, whether it was made in 1979 or

yesterday.  

 

--- Rainer.Facius at dlr.de wrote:

 

> John:

> 

>  

> 

> Taken at face value you might speculate that

> increased (mainly) Radon exposure decreases lung

> cancer incidence (Badgastein vs. Salzburg). Yet the

> rather short paper does not present sufficient facts

> to make that case. However, I reproduce a reference

> which I gave you already recently which many years

> ago found already genotoxic evidence about what an

> underlying mechanism might be.

> 

>  

> 

> "It is suggested that the shape of the dose-response

> curve at these very low levels of radiation [at

> Badgastein] may result from the induction of repair

> enzymes." (already in 1979!)

> 

> Pohl-Rüling J, Fischer P, The dose-effect

> relationship of chromosome aberrations to alpha and

> gamma irradiation in a population subjected to an

> increased burden of natural radioactivity. Radiation

> Research 80(1979)61-81

> 

>  

> 

> BTW, Pohl-Rühling belongs to the luminaries in her

> field.

> 

>  

> 

> Regards, Rainer 

> 

>  

> 

> 

> ________________________________

> 

> Von: John Jacobus [mailto:crispy_bird at yahoo.com]

> Gesendet: Mo 22.08.2005 18:54

> An: Facius, Rainer; jimm at WPI.EDU; rad-sci-l at WPI.EDU;

> radsafe at radlab.nl

> Betreff: Re: [ RadSafe ] AW: Gasteiner Heilstollen

> for holiday!?

> 

> 

> 

> Ranier,

> Would you then conclude that increased annual doses

> of

> radiation do not have a noticable effect on cancer

> rates? 

> 

> --- Rainer.Facius at dlr.de wrote:

> 

> > Jim:

> >

> > 

> >

> > "The percentage of all cancer deaths relative to

> all

> > deaths in

> > Badgastein during the years 1947-2000 was 21%, the

> > same value as in Bad

> > Hofgastein [a nearby control area] despite the

> > annual doses being three

> > times higher. Furthermore, the number of all

> > cancers, especially lung

> > cancer, in Bad Gastein is lower than the expected

> > value for the province

> > of Salzburg, despite the annual doses being four

> > times higher."

> >

> > 

> >

> > Pohl-Ruehling J, Hofmann W,

> >

> > Investigation of cancer mortality in the Gastein

> > Valley, an area of

> > high-level natural radiation.

> >

> > International Congress Series 1236(2002)27-29

> >

> > 

> >

> > Regards, Rainer

> >

> >

> > ________________________________

> >

> > Von: owner-rad-sci-l at WPI.EDU

> > [mailto:owner-rad-sci-l at WPI.EDU] Im Auftrag

> > von Muckerheide, James

> > Gesendet: Montag, 22. August 2005 16:19

> > An: rad-sci-l at WPI.EDU; radsafe at radlab.nl

> > Betreff: Gasteiner Heilstollen for holiday!?

> >

> >

> >

> > Friends,

> >

> > 

> >

> > In the 'Travel' section of the Irish

> Independent...

> > :-)

> >

> > 

> >

> > ...which says nothing about the long-term lung

> > cancer effect!

> >

> > 

> >

> > Regards, Jim Muckerheide

> >

> > ===================

> >

> > 

> >

> > DESTINATIONS : Build up your immunity on holidays

> >

> > Saturday August 20th 2005

> >

> >  . . .

> 

> +++++++++++++++++++

> "Every now and then a man's mind is stretched by a

> new idea and never shrinks back to its original

> proportion." -- Oliver Wendell Holmes, Jr.

> 

> -- John

> John Jacobus, MS

> Certified Health Physicist

> e-mail:  crispy_bird at yahoo.com

> 

> 

>                

> ____________________________________________________

> Start your day with Yahoo! - make it your home page

> http://www.yahoo.com/r/hs

> 

> 

> 

> 

> 

 

 

+++++++++++++++++++

"Every now and then a man's mind is stretched by a new idea and never shrinks back to its original proportion." -- Oliver Wendell Holmes, Jr.

 

-- John

John Jacobus, MS

Certified Health Physicist

e-mail:  crispy_bird at yahoo.com

 

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