Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mutations linked to genetic disorders shed light on a crucial DNA repair pathway

10.08.2015

Dividing cells are prone to errors, and so they must be prepared to summon sophisticated emergency systems to deal with potential damage. One type of division-derailing mishap can occur when assault by certain chemicals causes two strands of DNA to permanently connect when they shouldn't, in what scientists call interstrand crosslinks (ICLs). Properly fixing these crosslinks is crucial to preventing cancer, maintaining tissues, and fertility.

To better understand how a cell finds and fixes these misplaced crosslinks, researchers at The Rockefeller University and their colleagues are examining the genomes of patients in whom the repair process is defective. In two separate studies, the most recent described in Molecular Cell on August 6, they have identified two new genes in which mutations can produce one such rare genetic disorder, Fanconi anemia, and so revealed new insights on this critical repair pathway.


To confirm that a defect in RAD51 interfered with cells' ability to fix misplaced links between DNA strands, researchers treated patient cells with an agent to cause such links to form. The cells failed to repair them, producing broken chromosomes that fused with one another (red arrows).

Credit: Laboratory of Genome Maintenance at The Rockefeller University/Molecular Cell

"Our work began, as it often does, with samples and histories from patients. In these cases, we had two patients who each represented a sort of mystery: They had symptoms of Fanconi anemia, but no genetic cause yet identified," says senior author Agata Smogorzewska, associate professor and head of the Laboratory of Genome Maintenance. "Our investigation led us to discover a defective RAD51 protein in one patient, and a similarly dysfunctional protein UBE2T in the other."

The genes that code for RAD51 and UBE2T -- along with many other genes linked to Fanconi anemia in previous studies -- contribute to a repair process known as interstrand crosslink repair, which fixes a misplaced attachment between two strands of DNA. Caused by chemical agents, including often used chemotherapies like cisplatin; chemicals called aldehydes that occur naturally within cells, and nitrous acid formed after eating nitrates, ICLs block the replication of DNA, making it impossible for cells to accurately copy their genomes as they divide. The ICL repair process is very sophisticated and uses multiple enzymes that cut away the connection between the DNA strands, freeing them up and allowing the cells to grow.

The genome is at constant risk of forming ICLs, and defects in the ICL repair pathway can produce a constellation of symptoms associated with Fanconi anemia: a predisposition to cancer, failure of the stem cells in bone marrow responsible for producing blood cells, infertility, as well as developmental defects.

In the RAD51 research, supported by the Starr Cancer Consortium, first author Anderson Wang, a postdoctoral fellow in the Smogorzewska laboratory and his colleagues set out to determine the cause of the Fanconi anemia-like symptoms of a girl in the university's International Fanconi Anemia Registry. When they sequenced the protein-coding genes in her genome, they found mutations in one of two copies of the gene for the protein RAD51 -- a surprising culprit. This protein was already known to be important for another DNA repair process, called homologous recombination, in which a missing section of DNA is replaced using its sister strand as a template. Homologous recombination is thought to be used during the last step of ICL repair, after the crosslink has been cut.

But because only one copy of the RAD51 gene was partially defective, her cells could still perform homologous recombination, but not ICL repair. If both copies of RAD51, which is essential for life, had been defective, the girl would never have been born.

To show that the defective copy of the RAD51 gene was indeed responsible for her symptoms, the researchers genetically engineered the patient's own cells to remove the defect, which restored their ability to fix ICLs. Further experiments on the patient's cells --including biochemical work conducted by coauthor Stephen Kowalczykowski's lab at the University of California, Davis -- lead the researchers to suspect that RAD51 plays a role outside of homologous recombination, by tamping down the activity of two enzymes that degrade the DNA at the ICL. When RAD51 is defective, these enzymes (DNA2 and WRN) become overly destructive.

In the UBE2T study, published July 7 in in Cell Reports, the team, including first author Kimberly Rickman, a biomedical fellow in Smogorzewska's lab, found that mutations in a gene for a protein named UBE2T explained the Fanconi anemia symptoms seen in another registry patient. While it was already known that UBE2T is involved in activating ICL repair, the discovery that these mutations could produce Fanconi anemia revealed the protein is an irreplaceable player in the pathway.

"Although we have discovered new causes for this devastating but very rare genetic disease, the implications of this work go much further. By identifying new disruptions to this repair pathway, we can better understand the mechanisms of an event that is crucial to every cell division -- a process that occurs constantly within the human body throughout a lifetime," Smogorzewska says.

Wynne Parry | EurekAlert!

Further reports about: DNA DNA repair Fanconi RAD51 Rockefeller anemia genes genetic disorders mutations recombination repair process symptoms

More articles from Health and Medicine:

nachricht The genes are not to blame
20.07.2018 | Technische Universität München

nachricht Targeting headaches and tumors with nano-submarines
20.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>