Navigation Links
TSRI scientists catch misguided DNA-repair proteins in the act
Date:5/22/2014

LA JOLLA, CA May 22, 2014 Accumulation of DNA damage can cause aggressive forms of cancer and accelerated aging, so the body's DNA repair mechanisms are normally key to good health. However, in some diseases the DNA repair machinery can become harmful. Scientists led by a group of researchers at The Scripps Research Institute (TSRI) in La Jolla, CA, have discovered some of the key proteins involved in one type of DNA repair gone awry.

The focus of the new study, published in the May 22, 2014 edition of the journal Cell Reports, is a protein called Ring1b. The TSRI researchers found that Ring1b promotes fusion between telomeresrepetitive sequences of DNA that act as bumpers on the ends of chromosomes and protect important genetic information. The scientists also showed inhibiting this protein can significantly reduce the burden on cells affected by such telomere dysfunction.

"We are very far from therapy, but I think a lot of the factors we've identified could play key roles in processing dysfunctional telomeres, a key event in tumorigenesis [cancer initiation]," said Eros Lazzerini Denchi, assistant professor at TSRI who led the study.

The Trouble with Telomeres

Humans are born with long telomeres, but these become shorter every time a cell in the body divides. With age, telomeres become very short, especially in tissues that have high proliferation rate.

That's when the problems start. When telomeres become too short, they lose their telomere protective cap and become recognized by the DNA repair machinery proteins. This can lead to the fusion of chromosomes "end-to-end" into a string-like formation.

Joined chromosomes represent an abnormal genomic arrangement that is extremely unstable in dividing cells. Upon cell division, joined chromosomes can rupture, creating new break points that can further re-engage aberrant DNA repair. These cycles of fusion and breakage cause a rampant level of mutations that are fertile ground for cancer.

"You basically scramble the genome, and then you have lots of chances to select very nasty mutations," said Lazzerini Denchi.

Setting a DNA Trap

To understand how to prevent these deleterious fusions, Lazzerini Denchi and his colleagues wanted to identify all the repair factors involved.

The researchers decided to set a trap. Using genetically engineered cells, the researchers were able to remove a telomere binding protein called TRF2. Without TRF2, telomeres are unprotected and DNA repair proteins are recruited to chromosome ends, where they promote chromosome fusions.

The researchers then trapped and isolated all the proteins they found bound to the telomeres. "It was like a fishing expedition, and the bait in our case was the telomeric DNA sequence," said Lazzerini Denchi.

Cristina Bartocci, a postdoctoral fellow in Lazzerini Denchi's lab at the time and first author of the new study, spent more than two years perfecting a technique to identify proteins that flocked to the telomeres. "It was a pretty challenging experiment to perform," she said.

The researchers then separated the proteins from the DNA sequences and sent the proteins to TSRI Professor John Yates's laboratory for mass spectrometry analysis. This analysis revealed 24 known repair proteins and 100 additional proteins whose role in dysfunctional telomeres had not been previously described.

The team then refined their search and took a closer look at the role of the repair factor protein called Ring1b. For the first time, the scientists were able to link Ring1b to the chromosome fusion process. Bartocci said the role of Ring1b in dysfunctional telomere repair was "pretty striking."

"If you don't have Ring1b, the process of fusing the chromosomes is not very efficient," said Lazzerini Denchi.

In addition to Ring1b, the team has found nearly 100 factors that might be related to errors in DNA damage repair. The next step in this research is to further refine the long list of DNA repair factors and study other proteins that could affect human health.


'/>"/>

Contact: Madeline McCurry Schmidt
madms@scripps.edu
858-784-9254
Scripps Research Institute
Source:Eurekalert  

Related medicine news :

1. Scientists seek answers with space station thyroid cancer study
2. MIPT scientists develop algorithm for anti-aging remedy search
3. Scientists reveal structural secrets of enzyme used to make popular anti-cholesterol drug
4. Scientists slow brain tumor growth in mice
5. UBC scientists find new way to mobilize immune system against viruses
6. Dartmouth scientists identify genetic blueprint for cancerous tumors of the appendix
7. Scientists decode epigenetic mechanisms distinguishing stem cell function and blood cancer
8. Scientists identify new protein in the neurological disorder dystonia
9. Scientists awarded grant to develop diagnostics for cancer, rheumatoid arthritis, colitis
10. Norwegian neuroscientists elected to National Academy of Sciences
11. NIH scientists establish monkey model of hantavirus disease
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
TSRI scientists catch misguided DNA-repair proteins in the act
(Date:4/28/2016)... ... April 28, 2016 , ... Amada Senior Care, premier provider of non-medical in-home ... – its San Antonio West location. Prior to entering the senior care industry, Amada ... opening of Amada San Antonio West will take place on Friday, April 29th. ...
(Date:4/28/2016)... ... April 28, 2016 , ... ... the development of miniature microphones and headsets announced today that the US Patent ... of integrating in-earphones into a structure. This innovative design creates a lightweight and ...
(Date:4/28/2016)... ... , ... Metabolic Nutrition today announced the upcoming launch of its ... Get Fit and Sports Expo in Orlando, Florida. Attended by pro athletes, ... 29-30, was selected as the perfect event to introduce the highly anticipated GlycoLoad. ...
(Date:4/28/2016)... ... April 28, 2016 , ... The Aging in ... has established an ICD-10-CM code for sarcopenia, giving it recognition for separate reporting and ... effective October 1, 2016. , Sarcopenia is defined as a combination of low muscle ...
(Date:4/28/2016)... ... April 28, 2016 , ... ... to those affected by a health insurance co-operative bankruptcy to receive their ... individuals can receive over 1,500 FDA-approved prescription medications from over 180 American ...
Breaking Medicine News(10 mins):
(Date:4/28/2016)... PUNE, India , April 28, 2016 /PRNewswire/ ... - Pipeline Review, H1 2016" is a report ... pipeline and helps strengthen R&D pipelines by identifying ... best-in-class products. Company Profiles discussed in ... Menarini Industrie Farmaceutiche Riunite Srl, AbbVie Inc., Abiogen ...
(Date:4/27/2016)... , Schweiz, April 27, 2016 /PRNewswire/ ... des Sachs CEO Forums in Zürich gab ... ihres führenden Wirkstoffkandidaten STR001 zur Erhaltung des ... eingesetzt wurde, bekannt. Für die umfassende Phase-II-Doppelblindstudie ... und Frankreich angeworben. STR001 wird während der ...
(Date:4/27/2016)...   , Total Sales Grow ... Clinical sales grow 16% year-over-year  , ... MKEAY) inventor of Cellvizio®, the multidisciplinary confocal laser endomicroscopy ... ended March 31, 2016 and provided an update on ... First Quarter 2016 Revenue Results by Category  ...
Breaking Medicine Technology: