Jane Skok: Choreography of allelic exclusion

Abstract

Antibody diversity is generated during B cell development by the rearrangement of variable (V), diversity (D), and joining (J) segments of immunoglobulin (Ig) genes. Both alleles of each Ig locus can initiate rearrangement, but only one allele successfully rearranges. As soon as this occurs, the other allele is prevented from following suit. This mechanism, known as allelic exclusion, guarantees that each B cell produces antibodies specific for just one antigen. In her laboratory at New York University (NYU), Jane Skok studies how exclusion is established. Figure 1 Jane Skok Skok's initial foray into research involved dissecting the genetics of the complement cascade with Ellen Solomon at Cancer Research UK (1). But immediately after earning her Ph.D., Skok left science to care for her ill child. When she returned nearly a decade later, she had to start from scratch. After getting up to speed with a Master's in immunology, she joined Amanda Fisher's lab, where she gravitated toward B cells and the question of allelic exclusion. Skok has since helped define some of the steps that make exclusion possible. She discovered that the excluded Ig allele gets sent to repressive DNA domains near the centromere, whereas the productive allele remains within accessible domains (2–4). She later focused on one of the more curious aspects of allelic exclusion. During rearrangement, the Ig locus contracts, allowing V, D, and J segments to get close to each other and join up. Skok found that the successful rearrangement of one allele triggers locus relaxation, thereby stopping rearrangement of the other allele (5). She is now hunting for the proteins and pathways that direct the contortion and movement of Ig loci.