Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

When Repair Services Fail

07.05.2013
Cells are generally able to repair damage to the genome by themselves. However, a defect in the genes controlling such repair mechanisms usually leads to severe diseases. University of Würzburg scientists have now discovered mutations of an unexpected gene in the case of Fanconi anemia.
They are rare, but have very serious consequences for the people concerned: Diseases that are associated with defects in DNA repair. Depending on which repair process is impaired, they lead to a great variety of disorders.

Rare, but dangerous: Xeroderma pigmentosum

In the case of the skin disease Xeroderma pigmentosum, for instance, certain proteins, called XP proteins, are pathologically altered or even missing in the first place. The patients are oversensitive to sunlight, especially to its UV component. Their skin reddens considerably after minimum exposure to sunlight; inflammations, ulcers and scars develop at a later stage. Other possible symptoms include benign or malignant skin tumors.

"If the disease occurs early in life, it typically involves a mutation in one of the so-called XP genes," explains Detlev Schindler, Professor at the Institute of Human Genetics of the University of Würzburg. The mutation leads to a defect in the encoded protein so that the cell is no longer able to remedy certain cases of DNA damage.

"In this case, the process affected is called nucleotide excision repair," says Schindler. This multistage excision and repair process usually enables the cells to remove UV-light-induced changes in the chemical structure of neighboring nucleobases – the so-called pyrimidine dimers. These would otherwise cause distortions in the helix structure of the DNA strand, compromising transcription and replication processes.
If a certain XP gene is mutated – scientists classify such cases as "Type F defects" – patients suffering from Xeroderma pigmentosum may also show untypical symptoms, ranging from kidney malformations to bone marrow failure to premature aging, scientifically known as progeria.

Publication in the American Journal of Human Genetics

Schindler and his colleagues at the Institute of Human Genetics were significantly involved in a study, published in the current issue of American Journal of Human Genetics, which reports on two patients suffering from Fanconi anemia caused by mutations of the XPF gene. "We were able to show that this type of the disease involves the nonfunctional repair of a different kind of DNA lesions, namely undesired crosslinks in the DNA double-strand," explains Schindler.

In the study, the researchers show that the XPF factor is a central element in the DNA repair network with a lot of functions. Various repair mechanisms might be impaired, depending on the specific location of the defects. "The repair of DNA single or double-strand lesions, of pyrimidine dimers or covalent interstrand crosslinks or all of the above might be compromised," explains Schindler.

This means that mutations in one single gene can cause three different genetic disorders: Xeroderma pigmentosum, Fanconi anemia or XFE progeroid syndrome. The scientists classify the untypical Xeroderma pigmentosum symptoms as transitional towards Fanconi anemia.

Fanconi anemia

Fanconi anemia is an inherited early-onset form of bone marrow failure, which is associated with a significantly increased risk of cancer even in young adulthood. In a joint project with study groups from Spain, the Netherlands, England and the USA, the study group of Detlev Schindler contributed to the clarification of the genetic causes of this disease. In recent years, the Würzburg study group participated in the identification of several new Fanconi anemia genes, briefly referred to as FANC genes.
Thus, scientists have already identified 16 FANC genes, which trigger this severe disease when they are defective. "If they themselves are subject to mutation as in the case of Fanconi anemia, the FANC genes cannot perform their function as 'caretaker genes', namely to recognize and remedy irregularities in the DNA double-helix, which is so essential for the vitality of our body cells," says Schindler.

Even if only a single one of the FANC genes is nonfunctional or dysfunctional, some damage to the genome will accumulate with the resulting adverse effect on health. "In order to grow old in good health as far as possible and to avoid cancer and anemia for as long as possible, we need intact FANC genes," the human geneticist explains.

Research on rare diseases

Why is it that researchers invest so much effort in studying such rare genetic diseases? "If these occur early in life, they are usually due to mutations of individual genes," says Schindler. In many cases, the respective genes are also involved in the causation of more common diseases that develop in older age. In the case of Alzheimer's disease, for instance, it has been shown that the rare early-onset forms of the disease occurring before the age of 50 are triggered by defects in individual genes. By studying the normal function of these "Alzheimer genes", researchers were able to identify the molecular mechanisms, which also underlie the much more common late-onset forms of Alzheimer's disease.

Research into Fanconi anemia also offers such an additional benefit: "While the deadly Fanconi anemia develops in people with two defective copies of a FANC gene, women with only one defective copy of a FANC gene have a significantly increased risk of getting breast and ovarian cancer in some cases," Schindler explains. This possibility is now being studied in the case of mutations in the newly detected FANC gene (XPF=FANCQ). The identification of the FANC genes, the defects of which trigger the rare Fanconi anemia, thus also contributed to a better understanding of both the causes and therapeutic options in familial cases of breast and ovarian cancer.
At the University of Würzburg, Professor Caroline Kisker and her study group at the Rudolf Virchow Center also conducts research into nucleotide excision repair with particular focus on the XPD protein. It was she who identified the structure of this protein, which is also connected to several diseases; she works in close collaboration with the human geneticists.

Mutations in ERCC4, encoding the DNA repair endonuclease XPF, cause Fanconi anemia. Massimo Bogliolo et al. American Journal of Human Genetics 92, 1-7, May 2, 2013 (electronically published ahead of print April 25, 2013, http://dx.doi.org/10.1016/j.ajhg.2013.04.002

Contact person

Prof. Dr. Detlev Schindler, T: +49 (0) 931 31-88075,
email: schindler@biozentrum.uni-wuerzburg.de

Gunnar Bartsch | idw
Further information:
http://www.uni-wuerzburg.de

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>