A DNA Repair Complex Controls Antibody Class Switching

Researchers have dissected the Mre11-Rad50-Nbs1 (MRN) complex of DNA repair enzymes to study how the different components interact during the "gene-shuffling” process that occurs when immune B cells begin antibody production.

Investigators from the University of Michigan (Ann Arbor, USA) used advanced genetic engineering techniques to create a line of mice that lacked the genes for the entire MRN complex in B lymphocytes or that possessed an intact complex, but containing mutant Mre11 lacking DNA nuclease activity.

The scientists used these lines of mice to trace the mechanism of class switch recombination (CSR), which allows the class of antibody produced by an activated B cell to change during a process known as isotype or class switching. During CSR, portions of the antibody heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype.

Results published in the July 26, 2009, online edition of the journal Nature Structural and Molecular Biology revealed that MRN deficiency conferred a strong defect in CSR, affecting both the classic and the alternative NHEJ (nonhomologous end joining) pathways. In contrast, absence of Mre11 nuclease activity caused a milder phenotype, revealing a separation of function within the complex.

"Class switch recombination represents a double-edged sword, being necessary for immune system function, but known to cause cancer when mistakes are made. We now understand that Mre11 and the MRN complex as a whole lie in the middle of this delicate balance,” explained senior author Dr. David O. Ferguson, assistant professor of pathology at the University of Michigan. "The link to cancer results from what is known to happen to DNA breaks at the immunoglobulin locus. On rare occasions, these special DNA breaks can recombine with distant sites in the genome, and result in chromosome translocations that cause cancer.”

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