Navigation Links
Study Shows How Defective DNA Repair Triggers Two Neurological Diseases
Date:1/14/2009

St. Jude scientists' findings in ataxia telangiectasia-like disease and Nijmegen breakage syndrome offer insight into the links between brain disease and cancer vulnerability in people carrying the diseases

MEMPHIS, Tenn., Jan. 14 /PRNewswire-USNewswire/ -- Scientists at St. Jude Children's Research Hospital have teased apart the biological details distinguishing two related neurological diseases--ataxia telangiectasia-like disease (ATLD) and Nijmegen breakage syndrome (NBS).

Both disorders arise from defects in a central component of the cell's machinery that repairs damaged DNA, but each disease presents with distinct pathologies. Defects in DNA repair dramatically increase the risk of cancer, which is found in NBS. However, NBS is also characterized by the occurrence of small brain size, or microcephaly, while in contrast, ATLD causes predominantly neurodegeneration.

The research involved the use of mouse models of each the diseases to analyze how the gene defects in ATLD and NBS give rise to the different pathologies. The researchers published their findings in the Jan.15, 2009, issue of the journal Genes & Development.

"Besides shedding light on the rare diseases, the findings may also help to understand how defective DNA repair can selectively affect different organs and how this leads to cancer in some situations," said Peter McKinnon, Ph.D., associate member of the St. Jude Department of Genetics and Tumor Cell Biology and the paper's senior author.

To explore the differences between ATLD and NBS, the researchers used mice engineered to have defects in the causative genes, which produce two proteins that help form a critical component of the DNA repair machinery, called the MRN complex. The MRN complex zeroes in on broken DNA segments and attaches to them. It then recruits another important DNA repair protein, called ATM, to launch the repair process. However, if the damage is too severe, ATM may also trigger programmed cell death called apoptosis. "It happens that defects in ATM also lead to a disease similar to ATLD, highlighting the connections between diseases resulting from defects in this DNA repair pathway," McKinnon said.

The mice engineered to mimic ATLD, like their human counterparts, had defective genes that produce a protein called Mre11; while NBS mice were engineered to have defects in the gene for the protein called Nbs1.

In their experiments, the researchers produced increased DNA-damage stress in the two types of engineered mice, either by using radiation or knocking out a key enzyme that stitches together broken DNA ends.

The researchers then compared the resulting pathologies in the two types of mice. The scientists found that the brain cells of the ATLD mice but not the NBS mice showed a resistance to apoptosis, meaning that the DNA-damaged cells were more likely to survive, even when crippled. Such cells would ultimately die, however, producing the neurodegeneration characteristic of ATLD in humans. In contrast, the NBS mice showed normal apoptosis, but because fewer brain cells survived, developed significantly smaller brains, like their human counterparts.

"Thus, these findings have allowed us to understand how these different mutations in this one DNA repair complex can lead to different neuropathological outcomes," McKinnon said. The findings could also lead to understanding how carriers of the disease genes are more prone to cancer.

"There is a suspicion that people who carry these mutations may be predisposed to cancer and also more susceptible to chemotherapy agents or even to standard X-rays," McKinnon said. "Those agents induce the type of DNA damage that requires the MRN complex and ATM for repair. More generally, studies of the MRN complex and ATM are fundamental to understanding how to prevent changes to DNA that lead to cancer.

"Understanding more about how these proteins signal and interact, and how different cells in the body transduce the DNA damage signal, is of fundamental biological importance," McKinnon said. "This knowledge is necessary not only for understanding DNA repair diseases but for understanding the broader implications of maintaining of the stability of DNA."

Other authors of this paper include Erin Shull, Youngsoo Lee, Jingfeng Zhao and Helen Russell (St. Jude); John Petrini and Travis Stracker (Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences); and Hironobu Nakane (formerly of St. Jude).

This research was supported in part by the National Institutes of Health, the National Cancer Institute and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.


'/>"/>
SOURCE St. Jude Children's Research Hospital
Copyright©2009 PR Newswire.
All rights reserved

Related medicine technology :

1. New Overall Survival Study Results Confirm Oral Xeloda(R) plus Oxaliplatin (XELOX) is Comparable to FOLFOX-4 for the First-Line Treatment of Advanced Colorectal Cancer
2. New Study First to Confirm Sandostatin LAR(R) Depot Controls Tumor Growth in Patients With Rare Gastrointestinal Tumors
3. VA-NIH Study Offers Hope for Parkinsons Patients
4. Uroplasty Highlights Results From Clinical Study on Macroplastique(R) for the Treatment of Stress Urinary Incontinence
5. Reproductive Partners Participates in New IVF Progesterone Delivery System Study
6. Idenix Pharmaceuticals Initiates Proof-of-Concept Study of IDX184 for the Treatment of Hepatitis C Virus (HCV)
7. InterMune to Conduct Conference Call and Webcast to Discuss Results of Triple Combination Study of ITMN-191
8. ANA598 Demonstrates Potent Antiviral Activity in an Early Clinical Study in HCV-Infected Patients
9. ELAD(R) Liver Support System Study Initiated at Multiple U.S. Centers
10. Study Demonstrates that AHCC(R) Enhances Immune System by Increasing the Production of Key Dendritic Cells
11. Study Finds DOXIL(R) Combination Therapy Delays Disease Progression for Patients With Metastatic Breast Cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/27/2017)...  International Biophysics Corporation, a global medical device manufacturer based ... 34% revenue growth in 2016 when compared to the previous ... growth was fueled by its AffloVest® sales in ... of its global sales of surgical product lines. ... enter our 25 th year in delivering high-quality, innovative ...
(Date:2/27/2017)... , Feb. 27, 2017  RegeneRx Biopharmaceuticals, ... clinical-stage drug development company focused on tissue protection, ... for RGN-137, GtreeBNT Co., Ltd., received a positive ... 3 clinical trial design for RGN-137 to treat ... healing gel that incorporates Thymosin beta 4 ("Tß4") ...
(Date:2/27/2017)... Leading Countries, Technologies and Companies The global ... CAGR of 8.9% from 2016-2021 and CAGR of 9.2% from 2021-2027. ... from 2016 to 2027. The market is estimated at $816m in ... ... to discover how you can exploit the future business opportunities emerging ...
Breaking Medicine Technology:
(Date:2/27/2017)... ... February 27, 2017 , ... ... last week. In addition, Discount Power's RCE (Residential Customer Equivalent) count exceeds ... 2014. The company had 800 customers and 2,250 RCEs at the time of ...
(Date:2/26/2017)... ... February 25, 2017 , ... The February 13, 2017, assassination of Kim ... over nerve agents and the deadly use of chemical weapons. Many questions exist about ... even small doses can be lethal. , Jay Jagannathan, M.D., of Michigan-based Jagannathan Neurosurgical ...
(Date:2/26/2017)... ... February 26, 2017 , ... IndustryArchive.Org . is announcing a new ... B2B Sellers will now only pay for B.A.N.T. quality sales leads based on the ... said, “Given the new reality that B2B buyers are controlling the sales process via ...
(Date:2/25/2017)... Viejo, CA (PRWEB) , ... February 25, 2017 , ... ... with ProSharpen Color tools from Pixel Film Studios. With ProSharpen Color users have total ... sliders to easily refine their color range. With color spectrum tools users can visually ...
(Date:2/24/2017)... ... February 24, 2017 , ... An in-depth computational analysis of genetic variants implicated ... to eight genes that may explain why susceptibility to one of the disorders could ... study published today in the journal npj Schizophrenia. , “There is a wealth ...
Breaking Medicine News(10 mins):