Repair Of DNA By Brca2 Gene Prevents Medulloblastoma
Brca2 gene guides the development of the embryonic nervous system by triggering repair of broken DNA in rapidly dividing cells, ensuring normal size and function and preventing medulloblastoma.
Investigators at St. Jude Children's Research Hospital have gained some of the first major insights into how certain genes known to prevent cancer also guide the normal development of the nervous system before birth and during infancy by repairing DNA damage.
The St. Jude researchers demonstrated that the Brca2 gene plays a dual role in the developing nervous system, eliminating errors in the DNA of newly made copies of chromosomes and suppressing the onset of the brain cancer medulloblastoma.
"Our study showed that the Brca2 gene acts as a surveillance mechanism that triggers repair of DNA that is damaged when the cell makes a duplicate set of its chromosomes each time it divides," said Peter McKinnon, Ph.D., associate member of Genetics and Tumor Cell Biology department at St. Jude. "The enormous rate of cell divisions during growth of the cerebellum greatly increases the risk of DNA damage. So the cell must have a way to ensure that the damage is quickly repaired to prevent the accumulation of abnormal cells that can cause abnormalities, such as medulloblastoma." McKinnon is senior author of a report on this work in the advanced online version of "The EMBO Journal" (doi: 10.1038/sj.emboj.7601703).
Researchers also discovered that another gene, ATM, plays a secondary but important role in protecting the developing nervous system by triggering apoptosis in cells that have stopped dividing but still contain DNA damage. ATM prevents these abnormal cells, called granule precursors, from becoming incorporated into the developing cerebellum. In this way, ATM plays a backup role in further ensuring normal gene function after the period of rapid growth is complete.
"Our work is a significant step in understanding the interplay of genes linked to DNA repair and their role in preventing disease," said Pierre-Olivier Frappart, Ph.D., a postdoctoral researcher in McKinnon's laboratory, who did much of the work on this project. "As more mouse models lacking specific genes in certain tissues become available, we'll be able to further determine the relationships among various DNA repair pathways during the development of the nervous system."