Molecular Mechanism of Hypermutation

This chapter focuses on somatic hypermutation, the remarkable process of targeted mutagenesis that alters variable region sequence. The mechanism of somatic hypermutation has not yet been deflned in complete molecular detail. Nonetheless, it explains how B cells use cell-type-speciflc factors to initiate an attack on the immunoglobulin (Ig) loci, and then employ ubiquitous repair and recombination pathways to modify DNA sequence. The chapter begins with an overview of how somatic hypermutation alters the DNA sequence, emphasizing the characteristics of hypermutated variable regions that are relevant in understanding the mechanism, and then discussing the hypermutation pathway itself, focusing on speciflc factors that may participate in hypermutation. A hypermutation pathway driven by the creation and repair of DNA breaks was originally suggested by evidence that targeted mutation of Ig genes could produce either untemplated or templated mutations. B cells have usurped conserved and ancient pathways for DNA repair in order to carry out the targeted mutagenesis of Ig genes. The universality of this pathway is highlighted by recent evidence, and is discussed in the chapter.