How exactly was the absence of BRCA1 leading to such a neural catastrophe? In a previous paper, the team showed that without the protein coded by the BRCA1 gene, DNA is not packaged properly, becoming fragile and more likely to break during DNA replication. In this new paper, the researchers reveal more about that mechanism, showing that without the protective ability of BRCA1, breaks in the DNA strands go unfixed, prompting the molecule ATM kinase to activate a cellular "suicide" pathway involving a protein called p53. This pathway helps to halt the replication of damaged cells and is important in cancer research.
"BRCA1 acts by conferring stability to the DNA and preventing it from breaking," says Carlos G. PerezGarcia, a Salk researcher in the Molecular Neurobiology Lab. "BRCA1 is important for all healthy cells."
When the researchers eliminated both BRCA1 and p53, they found the neurons grew at a normal rate, but still disorderly, with cells pointed in the wrong direction.
"In this scenario, we recover a lot of neurons but there's still a lot of abnormalities, such as cells that are sideways and pointed the wrong direction," says Gerald Pao, who, along with Quan Zhu and PerezGarcia, is a primary contributor to the paper and Salk researcher.
This observation led the team to propose that BRCA1 has an additional role in assisting neurons in orienting: the gene acts on the centromere of DNAessentially an anchor for the chromosome arms essential in cell replicationto tell the new cell in which direction to grow, providing guidance in developing the brain's organized layers.
"It is remarkable that BRCA1 has such a significant effect on the brain, especially size. This work leads us to a better understanding of how to protect neurons," says Verma, who is also the Irwin and Joan Jacobs Cha
|Contact: Chris Emery|