Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

DNA repair in mammal embryos is a matter of timing

20.06.2006
Hints to origin of many cancers is revealed as St. Jude finds that the two pathways used to repair chromosome breaks are active at different times in cell development

Investigators at St. Jude Children's Research Hospital have discovered that the cells of the developing nervous system of the mammalian embryo have an exquisite sense of timing when it comes to fixing broken chromosomes: the cells use one type of repair mechanism during the first half of development and another during the second half.

The team also showed that blocking a repair pathway causes the cell to commit suicide, a process called apoptosis; and that preventing this attempt at apoptosis keeps the damaged cell alive and able to become cancerous. Moreover, the type of cancer that develops depends on which repair pathway was originally disrupted.

These findings reflect the meticulous timing of an important aspect of embryo development and help to explain the origin of a variety of cancers from muscle tumors to brain tumors, researchers said. A report on these results appears in the online prepublication issue of Proceedings of the National Academy of Science.

Specifically, the St. Jude researchers showed that the DNA repair pathway called homologous recombination (HR) works primarily during the first half of embryo development, when many cells are dividing inside the growing body. In contrast, the pathway called non-homologous end joining (NHEJ) becomes an important repair mechanism midway through development, when cells begin to assume their final form and take on specific roles.

HR and NHEJ repair a type of DNA damage called a double-strand break (DSB), which cuts completely through the DNA. DNA exists as two individual strands that associate to form its double-stranded, twisted-ladder--shaped structure.

The researchers also discovered that a protein called ATM is required for apoptosis that is triggered by blocking NHEJ. However, apoptosis triggered by blocking HR does not require this protein. ATM is a critical DNA damage-signaling factor that is required to prevent a severe human neurodegenerative syndrome called ataxia telangiectasia. This new work points to the specific DNA repair pathway that ATM is required to monitor in order to prevent neurodegeneration.

The HR pathway fixes a broken chromosome by using that chromosome's exact "twin" as a blueprint to guide the repair job, according to Peter McKinnon, Ph.D., an associate member of Genetics and Tumor Cell Biology at St. Jude and senior author of the PNAS paper. However, such twins only exist in cells that are preparing to divide into two new cells, a process called mitosis, he noted. Then, as the cell starts to divide, each member of the sister chromatid pair moves into a different new cell.

Because HR is active only during the first half of embryo development, it is the critical repair pathway for the rapidly multiplying precursor and stem cells--cells that populate the body during early development with "daughter" cells--that later take on specific roles, according to researchers.

"Therefore, if HR-related apoptosis is blocked during the early part of embryo development, precursor and stem cells are affected. And since those cells give rise to many different types of cells and tissues, many different types of cancers can arise, such as skin cancer and sarcomas (cancers of bone, cartilage, fat, muscle or blood vessels)," McKinnon said.

But as cells acquire specialized structures and functions, they stop dividing and no longer produce sister chromatids. "When cells begin assuming specific roles in the brain, they stow away most of their chromosomes into tightly wrapped strings of DNA and use only those genes required to survive and allow them to perform these roles," McKinnon explained. "In the absence of sister chromatids to use as blueprints, the NHEJ repair pathway uses various chemical means to join the broken ends of DNA strands."

Since the cell uses NHEJ only when many cells are becoming specialized, cancers that arise in the absence of this pathway are more specific, such as cancer of a type of cell that produces only immune cells called B lymphocytes. The wide variety of cancers that can form represents the fact that HR and NHEJ are important throughout the developing body, and not just in the developing nervous system.

An intriguing exception to the timing of HR and NHEJ during nervous system development is the development of medulloblastoma, a tumor in children that arises in the lower part of the brain called the cerebellum, McKinnon said. The infant cerebellum is still undergoing both rapid growth in the number of cells as well as specialization of many cells, he noted. "That means this part of the brain uses both HR and NHEJ to repair broken chromosomes, so disruption of either mechanism can cause cancer in this area of the brain."

The St. Jude team studied the roles of the two repair pathways using mice that lacked either the gene Xrcc2, which is critical for the HR pathway, or Lig4, which is critical for the NHEJ pathway.

Bonnie Kourvelas | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>