Protein prevents DNA damage in the developing brain and might 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.
Provided by St. Jude Children's Research Hospital
- Scientists track impact of DNA damage in the developing brain Jul 27, 2009 | not rated yet | 0
- 'Cheater' Cells May Spur Cancer Growth Apr 01, 2010 | not rated yet | 0
- Repair of DNA by Brca2 gene prevents medulloblastoma May 21, 2007 | not rated yet | 0
- Study shows how defective DNA repair triggers 2 neurological diseases Jan 15, 2009 | not rated yet | 0
- Adult stem cells carry their own baggage: Epigenetics guides stem cell fate Jun 30, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization ...
Neuroscience 4 hours ago | 5 / 5 (2) | 0
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
Neuroscience 4 hours ago | 3 / 5 (1) | 2
One of the major frontiers of modern science is a comprehensive understanding of the human brain and its functions to guide the development of new technologies in information and communication. In a major announcement for ...
Neuroscience 5 hours ago | 1 / 5 (1) | 0
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
Neuroscience 20 hours ago | 4.9 / 5 (9) | 0 |
(Medical Xpress)—The human brain is able to identify individuals' voices by comparing them against an internal 'average voice' prototype, according to neuroscientists.
Neuroscience May 23, 2013 | 3 / 5 (2) | 2 |
(HealthDay)—We've all seen them: the surfers who race to the beach when a hurricane hits, the guy who decides to ride out the storm in his overmatched boat, the tornado chasers who fearlessly steer their ...
1 hour ago | not rated yet | 0
(HealthDay)—New evidence-based guidelines provide guidance on medical and surgical methods for second-trimester abortion and management of associated complications, according to a practice bulletin published ...
46 minutes ago | not rated yet | 0
(HealthDay)—More than one in four of those eligible for new premium assistance tax credits under the Affordable Care Act (ACA) do not have a checking account and will not be able to receive premiums from ...
36 minutes ago | not rated yet | 0
(HealthDay)—Comorbid conditions often accompany alopecia areata, according to a study published online May 22 in JAMA Dermatology.
16 minutes ago | not rated yet | 0
(HealthDay)—As a world-class golfer, Stacy Lewis' accomplishments are remarkable. But it was a physical challenge in her childhood that defined her ascent to the top of her sport.
56 minutes ago | not rated yet | 0
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
1 hour ago | not rated yet | 0 |