Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor

24.04.2012
St. Jude Children's Research Hospital scientists discovered that the protein TopBP1 is indispensible for preventing the accumulation of DNA damage early in brain formation and might also serve as a tumor suppressor

St. Jude Children's Research Hospital scientists have rewritten the job description of the protein TopBP1 after demonstrating that it guards early brain cells from DNA damage. Such damage might foreshadow later problems, including cancer.

Researchers showed that cells in the developing brain require TopBP1 to prevent DNA strands from breaking as the molecule is copied prior to cell division. Investigators also reported that stem cells and immature cells known as progenitor cells involved at the beginning of brain development are more sensitive to unrepaired DNA damage than progenitor cells later in the process. Although more developmentally advanced than stem cells, progenitor cells retain the ability to become one of a variety of more specialized neurons.

"Such DNA strand breaks have great potential for creating mutations that push a normal cell toward malignancy," said Peter McKinnon, Ph.D., a St. Jude Department of Genetics member and the paper's senior author. "When we selectively knocked out TopBP1 in mice, the amount of DNA damage we saw suggests that TopBP1 is likely to be a tumor suppressor. We are exploring that question now."

The work appeared in the April 22 online edition of the scientific journal Nature Neuroscience. The research builds on McKinnon's interest in DNA repair systems, including the enzymes ATM and ATR, which are associated with a devastating cancer-prone neurodegenerative disease in children called ataxia telangiectasia, and a neurodevelopmental disorder called Seckel syndrome.

TopBP1 was known to activate ATR. Previous laboratory research by other investigators also suggested that activation made TopBP1 indispensable for DNA replication and cell proliferation. This study, however, showed that was not the case. Most progenitor cells in the embryonic mouse brain kept dividing after investigators switched off the TopBP1 gene.

"We showed that rather than being fundamentally important for building the machinery of replication, TopBP1's role is to monitor DNA damage and act when DNA damage occurs during replication," McKinnon said. The results offer insight into normal brain development, DNA damage repair mechanisms and cancer biology.

For this study, researchers tracked the impact of TopBP1 loss in progenitor cells at different stages in the developing mouse brain. The damage was most severe when the protein was knocked out in early progenitor cells. These rapidly dividing cells yield the next generations of progenitor cells that give rise to structures in the cortex involved in memory, vision, movement and sensation. When TopBP1 was silenced in the early progenitor cells, the cortex never developed. When TopBP1 was knocked out a day or two later in progenitor cells responsible for completing brain and nervous system development, the defects were present but less severe.

The progenitor cells that were created following the loss of TopBP1 were equally riddled with broken strands of DNA. In both the early and later progenitor cells, unrepaired DNA damage switched on the p53 gene that activated the cell's suicide pathway.

Researchers used low-dose radiation to show that early progenitor cells were more sensitive to the DNA strand breaks than were progenitor cells created a day or two later. Although the cells suffered comparable damage, the damage was more likely to induce cell suicide in the earliest progenitor cells. "This raises the likelihood that there is a different threshold to DNA damage in the early-born progenitors," researchers noted.

McKinnon added: "These early progenitor cells give rise to the cells that go on to make various brain structures, so it is really important that there are no errors in the blueprint of these starting cells. These findings show that TopBP1 plays a critical role in maintaining the integrity of the genome."

TopBP1 is not the only protein responsible for repairing broken DNA strands, but this study suggests it plays a unique role. When researchers turned off two other key repair factors, the proteins Lig4 and Xrcc1, in the cortex of developing mice, the loss resulted in much less severe defects than when TopBP1 was lost.

The study's first author is Youngsoo Lee of St. Jude. The other authors are Sachin Katyal, Susanna Downing, Jingfeng Zhao and Helen Russell, also of St. Jude.

The work was supported in part by the National Institutes of Health and ALSAC. Katyal is a Neoma Boadway AP Endowed Fellow.

St. Jude Children's Research Hospital

Since opening 50 years ago, St. Jude Children's Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more have been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. To learn more, visit www.stjude.org. Follow us on Twitter @StJudeResearch.

Summer Freeman | EurekAlert!
Further information:
http://www.stjude.org

More articles from Health and Medicine:

nachricht Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

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: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>