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!
Designer cells: artificial enzyme can activate a gene switch
22.05.2018 | Universität Basel
Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
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...
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...
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...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
22.05.2018 | Life Sciences
22.05.2018 | Earth Sciences
22.05.2018 | Trade Fair News