Critical protein prevents DNA damage from persisting through generations

A protein long known to be involved in protecting a cell from genetic damage has been found to play an even more important role in protecting the cell’s offspring. New research shows that the protein, known as ATM, is not only vital for helping repair double-stranded breaks in the DNA of immune cells, but is also part of a system that prevents genetic damage from being passed on when the cells divide.

Early in the life of B lymphocytes — the immune cells responsible for hunting down foreign invaders and labeling them for destruction — they rearrange their DNA to create various surface receptors that can accurately identify different intruders, a process called V(D)J recombination. Now, in a study published online in the journal Cell, Rockefeller University professor Michel Nussenzweig, in collaboration with his brother Andre Nussenzweig at the National Cancer Institute and their colleagues, shows that when the ATM protein is absent, chromosomal breaks created during V(D)J recombination go unrepaired, and checkpoints that normally prevent the damaged cell from replicating are lost.

Normal lymphocytes contain a number of restorative proteins, whose job it is to identify chromosomal damage and repair it or, if the damage is irreparable, prevent the cell from multiplying. Earlier research by Andre and Michel Nussenzweig had identified other DNA repair proteins that are important during different phases of a B lymphocyte’s life. It was during one of these studies, which examined genetic damage late in the life of a B cell, that they came across chromosomal breaks that could not be explained.

So the researchers began to look into the potential role of V(D)J recombination. “We were not expecting it to be responsible for the breaks we were seeing,” says Michel, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology. “Because for it to be responsible, the breaks would have had to happen early on; the cell would have to divide, mature, maintain the breaks and stay alive with broken chromosomes.” This, in fact, was precisely what they found.

The ATM protein appears to have two roles in a B cell: It helps repair the DNA double-strand breaks, and it activates the cell-cycle checkpoint that prevents genetically damaged cells from dividing. “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,” says Michel, who’s also a Howard Hughes Medical Institute investigator.

Since the ATM protein is mutated in a number of lymphomas — cancers of the lymph and immune system — the new finding suggests to researchers that the lymphocytes could have been living with DNA damage for a long time, and that this damage likely plays a role in later chromosomal translocations, rearrangements of genetic materials that can lead to cancer.

Michel and his brother, who’ve been collaborators for more than a decade, intend to pursue the molecular mechanisms by which these chromosomal translocations occur. “I think it’s important to understand them,” he says, “because eventually we might be able to prevent these dangerous chromosome fusions.”

Citation: Cell: June 28, 2007

Source: Rockefeller University

Related stories:

You can be replaced: Immune cells compensate for defective DNA repair factor
A new mouse model has provided some surprising insight into XLF, a molecule that helps to repair lethal DNA damage. The research, published by Cell Press in the September 5th issue of the journal Molecular Cell, suggests that although XLF shares many properties with well known DNA repair factors, certain cells of the immune system possess an unexpected compensatory mechanism that that can take over for nonfunctional XLF.
HIV conquers immune system faster than previously realized
New research into the earliest events occurring immediately upon infection with HIV-I shows that the virus deals a stunning blow to the immune system earlier than was previously understood. According to scientists at Duke University Medical Center, this suggests the window of opportunity for successful intervention may be only a matter of days – not weeks – after transmission, as researchers had previously believed.
Real-time observation of the DNA-repair mechanism
For the first time, researchers at Delft University of Technology have witnessed the spontaneous repair of damage to DNA molecules in real time. They observed this at the level of a single DNA molecule. Insight into this type of repair mechanism is essential as errors in this process can lead to the development of cancerous cells. Researchers from the Kavli Institute of Nanoscience Delft are to publish an article on this in the leading scientific journal Molecular Cell.
Stem cells and cancer: cancer pathways that also control the adult stem cell population
Speaking today (10 April) at the UK National Stem Cell Network Annual Science Meeting in Edinburgh, Professor Alan Clarke from Cardiff University describes his work to investigate a mechanism that normally drives adult stem cells to repair the intestine.
New technique takes a big step in examination of small structures
A team led by a Purdue University researcher has achieved images of a virus in detail two times greater than had previously been achieved. Wen Jiang, an assistant professor of biological sciences at Purdue, led a research team that used the emerging technique of single-particle electron cryomicroscopy to capture a three-dimensional image of a virus at a resolution of 4.5 angstroms.
New study reveals for first time how BRCA1 mutations cause breast cancer
An international team of researchers led by Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center and Sweden’s Lund University has, for the first time, revealed how mutations in the BRCA1 gene lead to breast cancer. Findings show that one way BRCA1 mutations cause cancer is by knocking out a powerful tumor suppressor gene known as PTEN.
Get in touch
When the genetic material inside a cell’s nucleus starts to fall apart, a protein called ATM takes charge and orchestrates the rescue mission. Surprisingly, for ATM to kick into full gear, the stretches of DNA flanking a chromosomal break are just as important as the damaged site itself, report scientists at the Salk Institute for Biological Studies.
Sensitivity of brain center for 'sound space' defined
While the visual regions of the brain have been intensively mapped, many important regions for auditory processing remain “uncharted territory.” Now, researchers at the Hebrew University of Jerusalem and elsewhere have identified a region responsible for a key auditory process — perceiving “sound space,” the location of sounds, even when the listener is not concentrating on those sounds.

News discussion:

General Science news