Hints as to why immunoglobulin (Ig) genes — which encode antibody molecules — are more frequently targeted for mutation than other genes are provided in a paper published online this week in Nature Immunology.
Ig genes are highly diversified by a programmed mutation process directed by an enzyme called activation-induced cytidine deaminase (AID). Although AID preferentially targets Ig genes, other genes can also be mutated by AID, often contributing to mutations that lead to the development of B cell lymphomas and other malignancies.
To ascertain what rules govern AID recruitment, Rafael Casellas and Michel Nussenzweig team up to map AID binding sites throughout the entire genome. Surprisingly, AID binding was promiscuous, binding to thousands of non-Ig genes at sites associated with stalled RNA polymerase complexes on transcriptionally active genes, which can explain off-target AID-mediated mutations. The Ig genes uniquely recruit another factor, called RPA, forming a complex that is associated with the higher mutation frequency seen for the Ig genes.