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New Role For Critical DNA Repair Molecule In Immune System

Date:
November 9, 2008
Source:
Rockefeller University
Summary:
The human immune system is a brilliantly adaptable weapon against foreign invaders. But it all depends on the work of specialized cells called lymphocytes that have made a risky evolutionary gambit to mutate their own DNA. New research published in Nature shows for the first time that a molecule devoted to DNA repair plays a broader role in this genetic reshuffling -- called recombination -- than scientists had thought.

Coming together. Sections of DNA known as loci (green and red dots, above) must be shuffled and recombined in order for immune cells to build receptors that recognize hostile substances. New research shows that a DNA repair molecule, 53BP1, is critical for this process to occur; without it (right), the loci remain separated.
Credit: Image courtesy of Rockefeller University

The human immune system is a brilliantly adaptable weapon against foreign invaders. But it all depends on the work of specialized cells called lymphocytes that have made a risky evolutionary gambit to mutate their own DNA. New research published in Nature shows for the first time that a molecule devoted to DNA repair plays a broader role in this genetic reshuffling — called recombination — than scientists had thought.

Because mistakes in recombination can have catastrophic consequences, the new research could help explain processes that lead to some of the most aggressive types of cancer, such as leukemia and B cell lymphomas.

Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, his brother Andrι Nussenzweig, a senior investigator at the National Institutes of Health Experimental Immunology Branch in the National Cancer Institute, and colleagues used genetically altered “knockout” mice that were missing the DNA repair molecule, known as 53BP1, to study how its absence would affect a specific type of genetic reshuffling called V(D)J recombination.

They found that the knockout mice had 50 percent fewer lymphocytes in their bone marrow and 80 percent fewer in their thymus, a collection of glands that helps produce specialized immune cells. The mice also had problems with the lymphocytes that remained. To combat infection, these cells must have receptors that can recognize a foreign substance when they encounter it, beginning the process of producing an antibody to fight it. In mice lacking 53BP1, however, the sections of DNA, or loci, that must recombine to build these receptors are farther apart than normal, making their recombination much less likely, the researchers found.

The lack of 53BP1 prevented the proper reshuffling of genetic material during recombination. Whenever a section of genetic material is cut loose in order to be recombined, it must be quickly reattached or else it risks migrating to another chromosome in a process called translocation, a common cause of cancer. In normal V(D)J recombination, that does not happen, but sometimes the genetic material that is being reshuffled does have to travel to a relatively distant place on its own chromosome. The researchers found that that process of long-distance DNA end-joining, happened 2.5 times less often in mice that lacked 53BP1.

And, when recombination falters, serious consequences follow. “Problems with these reactions lead to immunodeficiencies and cancer,” says Nussenzweig, who is also a Howard Hughes Medical Institute investigator. Preventing 53BP1 from repairing DNA has been linked to Riddle Syndrome, a recently diagnosed immunodeficiency disorder, and it is likely related to many others, he adds. “We would like to know now whether any break in chromosomes at a distance, including translocations, is facilitated by 53BP1. We suspect that it will be and we want to know how. My colleague Titia de Lange has been looking at this and has demonstrated that 53BP1 plays a role in the motility of a broken DNA locus.”

De Lange’s research, also recently published in Nature, shows that one way that 53BP1 repairs damaged DNA is by helping the displaced genetic material move to its proper destination.

Nature online: October 19, 2008


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Cite This Page:

Rockefeller University. "New Role For Critical DNA Repair Molecule In Immune System." ScienceDaily. ScienceDaily, 9 November 2008. <www.sciencedaily.com/releases/2008/10/081030201615.htm>.
Rockefeller University. (2008, November 9). New Role For Critical DNA Repair Molecule In Immune System. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2008/10/081030201615.htm
Rockefeller University. "New Role For Critical DNA Repair Molecule In Immune System." ScienceDaily. www.sciencedaily.com/releases/2008/10/081030201615.htm (accessed October 23, 2014).

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