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 Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

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: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>