Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


When Repair Services Fail

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,

Contact person

Prof. Dr. Detlev Schindler, T: +49 (0) 931 31-88075,

Gunnar Bartsch | idw
Further information:

More articles from Life Sciences:

nachricht Chimpanzees Shed Light on Origins of Human Walking
09.10.2015 | Stony Brook University

nachricht In “Cell”: Floppy but fast
09.10.2015 | Heidelberger Institut für Theoretische Studien gGmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Reliable in-line inspections of high-strength automotive body parts within seconds

Nondestructive material testing (NDT) is a fast and effective way to analyze the quality of a product during the manufacturing process. Because defective materials can lead to malfunctioning finished products, NDT is an essential quality assurance measure, especially in the manufacture of safety-critical components such as automotive B-pillars. NDT examines the quality without damaging the component or modifying the surface of the material. At this year's Blechexpo trade fair in Stuttgart, Fraunhofer IZFP will have an exhibit that demonstrates the nondestructive testing of high-strength automotive body parts using 3MA. The measurement results are available in a matter of seconds.

To minimize vehicle weight and fuel consumption while providing the highest level of crash safety, automotive bodies are reinforced with elements made from...

Im Focus: Kick-off for a new era of precision astronomy

The MICADO camera, a first light instrument for the European Extremely Large Telescope (E-ELT), has entered a new phase in the project: by agreeing to a Memorandum of Understanding, the partners in Germany, France, the Netherlands, Austria, and Italy, have all confirmed their participation. Following this milestone, the project's transition into its preliminary design phase was approved at a kick-off meeting held in Vienna. Two weeks earlier, on September 18, the consortium and the European Southern Observatory (ESO), which is building the telescope, have signed the corresponding collaboration agreement.

As the first dedicated camera for the E-ELT, MICADO will equip the giant telescope with a capability for diffraction-limited imaging at near-infrared...

Im Focus: Locusts at the wheel: University of Graz investigates collision detector inspired by insect eyes

Self-driving cars will be on our streets in the foreseeable future. In Graz, research is currently dedicated to an innovative driver assistance system that takes over control if there is a danger of collision. It was nature that inspired Dr Manfred Hartbauer from the Institute of Zoology at the University of Graz: in dangerous traffic situations, migratory locusts react around ten times faster than humans. Working together with an interdisciplinary team, Hartbauer is investigating an affordable collision detector that is equipped with artificial locust eyes and can recognise potential crashes in time, during both day and night.

Inspired by insects

Im Focus: Physicists shrink particle accelerator

Prototype demonstrates feasibility of building terahertz accelerators

An interdisciplinary team of researchers has built the first prototype of a miniature particle accelerator that uses terahertz radiation instead of radio...

Im Focus: Simple detection of magnetic skyrmions

New physical effect: researchers discover a change of electrical resistance in magnetic whirls

At present, tiny magnetic whirls – so called skyrmions – are discussed as promising candidates for bits in future robust and compact data storage devices. At...

All Focus news of the innovation-report >>>



Event News

EHFG 2015: Securing healthcare and sustainably strengthening healthcare systems

01.10.2015 | Event News

Conference in Brussels: Tracking and Tracing the Smallest Marine Life Forms

30.09.2015 | Event News

World Alzheimer`s Day – Professor Willnow: Clearer Insights into the Development of the Disease

17.09.2015 | Event News

Latest News

Navigating the unknown

09.10.2015 | Information Technology

New Artificial Cells Mimic Nature’s Tiny Reactors

09.10.2015 | Materials Sciences

Chimpanzees Shed Light on Origins of Human Walking

09.10.2015 | Life Sciences

More VideoLinks >>>