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 Great apes communicate cooperatively
25.05.2016 | Max-Planck-Institut für Ornithologie

nachricht Rice study decodes genetic circuitry for bacterial spore formation
24.05.2016 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Computational high-throughput screening finds hard magnets containing less rare earth elements

Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.

The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...

Im Focus: Atomic precision: technologies for the next-but-one generation of microchips

In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.

In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...

Im Focus: Researchers demonstrate size quantization of Dirac fermions in graphene

Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices

Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.

Im Focus: Graphene: A quantum of current

When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene

In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...

Im Focus: Transparent - Flexible - Printable: Key technologies for tomorrow’s displays

The trend-forward world of display technology relies on innovative materials and novel approaches to steadily advance the visual experience, for example through higher pixel densities, better contrast, larger formats or user-friendler design. Fraunhofer ISC’s newly developed materials for optics and electronics now broaden the application potential of next generation displays. Learn about lower cost-effective wet-chemical printing procedures and the new materials at the Fraunhofer ISC booth # 1021 in North Hall D during the SID International Symposium on Information Display held from 22 to 27 May 2016 at San Francisco’s Moscone Center.

Economical processing

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking 4.0: International Laser Technology Congress AKL’16 Shows New Ways of Cooperations

24.05.2016 | Event News

Challenges of rural labor markets

20.05.2016 | Event News

International expert meeting “Health Business Connect” in France

19.05.2016 | Event News

 
Latest News

LZH shows the potential of the laser for industrial manufacturing at the LASYS 2016

25.05.2016 | Trade Fair News

Great apes communicate cooperatively

25.05.2016 | Life Sciences

Thermo-Optical Measuring method (TOM) could save several million tons of CO2 in coal-fired plants

25.05.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>