Studying DNA Damage Through the Generations

Author:  Wang Andrew

Date:  July 2007

Researchers at Rockefeller University, Howard Hughes Medical Institute, and the National Cancer Institute, led by Michel Nussenzweig and his brother Andre Nussenzweig and their colleagues, have discovered this month that a protein, known as ATM has new and extraordinary abilities. Not only does it help repair breaks in the double-stranded structure of DNA in immune cells, but it also prevents genetic damage from being passed on when the cells divide. This new discovery could potentially influence future studies of cancers of the lymph and immune system, known collectively as lymphomas, as ATM has a crucial role in the life cycle of immune cells.

In the recent study, the ATM protein was found to be play a significant role in a process known as V(D)J recombination. V(D)J recombination occurs when the DNA of immune cells responsible for labelling foreign invaders for destruction is re-arranged, creating different surface receptors to accurately identify different invaders. It was found that if ATM was missing, chromosomal breaks that occur during V(D)J recombination are left uncorrected and the protective measures preventing the damaged cell from replicating are lost.

"We were not expecting it to be responsible for the breaks we were seeing," said Michel, "ATM is required for a B cell to know that it has a broken chromosome. And if it doesn't know that it seems to be able to keep on going." Now, research has clearly shown that ATM has two roles in the B cell: it helps to repair breaks in DNA and also activates the cell cycle checkpoint that prevents genetically damaged cells from replicating.

The ATM protein has been found to be mutated in a number of lymphomas. This suggests that accumulation of lymphocytes with damaged DNA may have caused chromosomal translocations, or re-arrangements of the DNA, resulting in cancer.

Michel and his brother intend to further pursue chromosomal translocations. "I think it's important to understand them," he said, "because eventually we might be able to prevent these dangerous chromosome fusions."

- By Andrew Wang.