In every cell, a group of proteins called caretakers keeps vigil for signs of DNA damage. If damage is encountered, these proteins act immediately to repair the DNA and preserve the stability of the genome. Although small in number, these proteins perform a vital function and protect against potentially catastrophic consequences such as cancer-causing mutations or chromosome rearrangements, a frequent cause of leukemias and lymphomas.
In the April 20, 2000, issue of the journal Nature , HHMI investigator Frederick W. Alt and colleagues at the Children's Hospital in Boston provide evidence that XRCC4, a member of a family of proteins called non-homologous end-joining proteins, is a new type of genomic caretaker.
In previous studies, Alt and his colleagues found that XRCC4 helps to rejoin the broken ends of double-stranded DNA. Such breaks in DNA can occur randomly as a result of exposure to ionizing radiation or in the course of normal lymphocyte development. Alt's group found that XRCC4 was needed to rejoin DNA in lymphocytes that undergo gene shuffling in the process of creating the vast repertoire of infection-fighting cells. Curiously, the researchers also found that XRCC4 was needed to mend damaged DNA in the developing brains of mice.
They reasoned that since the well-known genome guardian p53 monitors the cell for breaks in DNA, it was possible that p53 was "seeing" the unrepaired broken ends of DNA in the neurons and marking those cells for death.
"Our educated guess proved out completely," said Alt. "When we got rid of p53 in the XRCC4-deficient mice, they survived through embryonic development. Also, their nervous systems appeared largely intact, and they showed normal behaviors, such as the ability to walk and eat."
"We knew that B and T immune cells in these mutant mice can't put the immune gene segments back together, and without such recombination the cells can't develop past their progenitor stage," said Alt.
"We don't yet know the reason for this translocation, whether there is a preferential breakage point, or whether there is a very strong selection for cells that are translocated at c-myc ," said Alt.
The scientists will also explore how the absence of XRCC4 or other components of the DNA-repair machinery affects developing neurons.
Nature