DNA Polß-deficient B cells switch more frequently when AID targets are sparse (IgG2a).

The spontaneous mutation of cytosine bases to uracils is corrected by a process that removes the wrong bases, cuts the DNA at the empty spots, and reinserts the correct bases. This normally efficient process fails in B cells that are switching from producing IgM to making other classes of antibodies. In these cells, cytosines are converted to uracils by the enzyme activation-induced deaminase (AID). The mutated DNA is cut normally, but the ends then recombine to produce new types of antibodies. Recombination thus occurs at the expense of repair.

The repair failure is blamed on DNA polymerase ß (Polß), whose job is to add back the correct nucleotides. Scientists have proposed that B cells undergoing class switching have too little Polß or that the damaged DNA sites are not accessible to the enzyme.

But Wu and Stavnezer now show that Polß is probably as productive in B cells as it is in other cell types. Polymerase levels were normal, and the enzyme found its way to damaged sites. Activated B cells lacking the polymerase had even more mutations—and more recombination events—than usual.

The team needed a new explanation. They hypothesized that recombination happens because AID creates too many damaged sites for Polß to repair. The absence of Polß caused a noticeable increase in recombination only in antibody genes with relatively few AID target sequences. Recombination events were abundant, however, in genes with lots of AID targets whether or not Polß was present. Thus Polß repairs AID-induced lesions, but can only fix so many.

Activated B cells need their repair machinery to protect themselves from unwanted mutations during antibody gene rearrangement. The authors speculate that, to switch antibody types, B cells thus have had to dilute the efficiency of the repair process by gaining more AID targets in antibody genes.

Related Article

DNA polymerase ß is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination

Xiaoming Wu and Janet Stavnezer
J. Exp. Med. 2007 204: 1677-1689. [Abstract] [Full Text] [PDF]