Student Theses and Dissertations

Yair Dorsett

Date of Award

2008

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Nussenzweig Laboratory

Abstract

Chromosome translocations between oncogenes and the immunoglobulin (Ig) region spanning the variable (V), diversity (D) and joining (J) genes (Ig V-JH region) are found in a number of mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences (RSSs) targeted by recombinase activating genes 1 and 2 (RAG1/2) during antigen receptor assembly in pre- B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing AID dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double strand break make up 6% of all the Ig V-JH region associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-JH translocations, we searched for such events in both IL6 transgenic (IL6 tg) and AID-/- IL6 tg mice. Our experiments demonstrate that AID is required for c-myc to Ig V-JH translocations induced by IL6. We also investigated the potential role of microRNAs (miRNAs) in AID mediated processes. MiRNAs are small non-coding RNAs that regulate vast networks of genes that share miRNA target sequences. To examine the physiologic effects of an individual miRNA in vivo we created a knock-in mouse that carries a mutation in the putative microRNA-155 (miR-155) target site in the 3’UTR of AID (AID155 mice). AID155 causes an increase in steady state AID mRNA and protein levels by increasing the half-life of the mRNA resulting in high levels of c-myc-IgH translocations. A similar but more pronounced translocation phenotype was also found in bic/miR-155 /- mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID.

Comments

A Thesis Presented to the Faculty of The Rockefeller University In Partial Fulfillment of the requirements for the degree of Doctor of Philosophy

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