Navigation Links
How defects in 1 gene cause 3 distinct and devastating human diseases
Date:5/29/2008

By studying heat-loving microbes, two research teams have gained new insight into how seemingly small differences in a single protein involved in DNA transcription and repair can lead to strikingly different genetic disorders in humans.

The two studies in the May 30th issue of Cell, a Cell Press publication, uncover the crystal structure and biochemical activity of an enzyme known as XPD helicase taken from Sulfolobus archaea, microbes distinct from bacteria that share many fundamental genes with humans. For reasons that had remained rather mysterious until now, point mutations in human XPDsometimes at neighboring sitescan spell the difference between cancer-prone xeroderma pigmentosa, the aging disorder known as Cockayne syndrome and another aging disorder called trichothiodystrophy.

If you consider the linear sequence of XPD and map the [disease-linked] point mutations onto it, there is nothing clear about why they would be causative for one of the three diseases or another, said Jill Fuss of The Scripps Research Institute. By having these structures for XPD, we suddenly see how it is working.

The protein from archaea is a simplified model, but that doesnt stop us learning a lot about the biology of the human enzyme, said Malcolm White of University of St Andrews, who led the other study. Archaeal protein structures are often very close matches to the equivalent proteins from humans, even though they diverged from one another three billion years ago. We can learn a lot about human health by looking deep into evolutionary time.

Archaea have particular similarities with humans and other eukaryotes in the way in which they process information, including DNA replication, transcription and repair, White explained. One of those common elements is XPD helicase, a component of a fundamental complex (known as TFIIH) with roles in initiating the transcription of genes into the templates for protein and in the repair of damaged DNA. In both instances, the helicase parts the two DNA strands at either the transcription start site or the site of DNA damage.

Defects in XPD are known to underlie xeroderma pigmentosa (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). Although people with all three diseases share a sensitivity to the sun, they differ greatly in their predispositions to cancer or accelerated aging, explained John Tainer, who led the Scripps study. XP patients show several 1000-fold increase in skin cancer, whereas neither CS nor TTD patients show an increase in the cancer incidence despite their sun sensitivity. Furthermore, both CS and TTD are premature aging diseases plus developmental disorders, with CS patients being more severely affected and exhibiting severe mental retardation from birth.

Both teams now have evidence to explain what separates the diseases despite their similar molecular causes. They find that XP-causing mutations in XPD all fall in sites where the helicase binds ATP (the energy currency of the cell) or DNA. Those alterations leave the enzyme unable to function in DNA repair. However, the overall effect on the structure of the enzyme is minimal. As such, the enzyme still fills its position in the TFIIH complex, allowing transcription to proceed. That inability to repair defects, leaves those with XP prone to developing cancer as mutations arise and go uncorrected.

In the case of TTD, the defect is quite different, White said. TTD-linked mutations are found all over the protein at points important to its interactions with other proteins. Therefore, those mutations leave the protein floppy, destabilizing the entire TFIIH complex and causing defects in both transcription and repair.

It is thought that the transcription defects protect against cancer, but lead to an increase in cell death and therefore the rapid aging symptoms seen in TTD patients, White said.

As for CS, Tainers group suggests it results when defects in XPD lock the protein into a rigid position. As a result, they said, the protein may stick in repair mode and cut out DNA at sites where it should be transcribing.

White agrees that CS seems to result from mutations that influence the XPD proteins flexibility. However, hes not yet sure exactly how that leads to the symptoms of CS.

The new insights into XPD point to the importance of whole proteins, not just their active sites.

Weve been able to characterize three activities together with the structure, Tainer said. Weve shown how mutations in the binding site alone can cause cancer. Scientists often thought it was just the active sites that were importantthat other changes wouldnt matter. But we see that other changes can lead to very severe defects.

The results also hold an important general lesson for the value of protein structure for understanding gene function. The results of the Human Genome Project have revealed associations between sequence mutations and particular diseases or disease risks, but in many cases we dont know why, Tainer said. As in the case of XPD, the protein structures may hold the key.


'/>"/>

Contact: Cathleen Genova
cgenova@cell.com
617-397-2802
Cell Press
Source:Eurekalert

Related medicine news :

1. Another Reason Not to Smoke While Pregnant: Birth Defects
2. Cell-surface sugar defects may trigger nerve damage in multiple sclerosis patients
3. Heart Defects Can Delay Babys Brain Development
4. Hazardous Advanced Micro Devices (A.M.D.) Clean Room Chemicals Caused Multiple Birth Defects, Lawsuit Alleges
5. Procedure to detect fetal heart defects is first automated use of 3-D ultrasound
6. For babies with heart defects, death risk is far lower at most experienced hospitals
7. Babies With Heart Defects Do Best at Hospitals With Most Experience
8. Congenital heart defects increasing among IVF twins
9. Folic Acid in the Food Supply Reduces Birth Defects, but May Cause Extra Cancers, Reports the Harvard Womens Health Watch
10. Reconstructing mandibular defects with bioengineered tooth and bone
11. The Childrens Hospital of Philadelphia Opens the Worlds First Delivery Unit for Mothers Diagnosed with Birth Defects in Fetus
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/12/2017)... ... ... Planet Fitness, one of the largest and fastest growing franchisors and operators ... location in Covington, LA at 401 N. U.S. Highway 190, in January of 2018. ... in the Holiday Square shopping center. Its location allows it to serve both Covington ...
(Date:10/12/2017)... ... October 12, 2017 , ... The American College of Medical Informatics (ACMI) ... FACMI, during the Opening Session of AMIA’s Annual Symposium in Washington, D.C. AMIA’s ... Morris F. Collen, a pioneer in the field of medical informatics, this prestigious award ...
(Date:10/12/2017)... ... October 12, 2017 , ... Dr. Parsa Mohebi, ... a medical article to the newly revamped Cosmetic Town journal section, ... hair transplant procedure known as Follicular Unit Extraction (FUE). , Dr. ...
(Date:10/12/2017)... ... October 12, 2017 , ... On Saturday, October 21, the Health & Wellness ... Moonlight to raise money for the American Heart Association Heart Walk. Teams of up ... work together to keep their treadmills moving for 5 hours. Treadmills will start at ...
(Date:10/12/2017)... ... 2017 , ... In the United States, single-family home owners ... New York, New Jersey, Massachusetts, Texas, Virginia, Connecticut, and California—the average is $7,000 ... property-tax rates, which contributes to the relatively lower cost of living in places ...
Breaking Medicine News(10 mins):
(Date:10/11/2017)... , Oct. 11, 2017  Caris Life Sciences ... on fulfilling the promise of precision medicine, today announced ... joined Caris, Precision Oncology Alliance™ (POA) as its 17 ... centers, the St. Jude Crosson Cancer Institute will help ... the use of tumor profiling, making cancer treatment more ...
(Date:10/10/2017)... Oct. 10, 2017   West Pharmaceutical Services, Inc. ... for injectable drug administration, today shared the results of ... for improving the intradermal administration of polio vaccines. The ... Summit in May 2017 by Dr. Ondrej Mach ... World Health Organization (WHO), and recently published in the ...
(Date:10/4/2017)... WESTWOOD, Mass. , Oct. 4, 2017  According to the Centers ... by the end of October . PhysicianOne Urgent Care is helping communities ... Westchester, NY , by offering no-cost* flu shots through ... , as mandated by certain health insurance regulations. ... The best time to get a flu shot is by ...
Breaking Medicine Technology: