Grant: $422,500 - National Institutes of Health - Sep. 29, 2009
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Award Description: B and T lymphocyte development is driven by V(D)J recombination, a process by which gene segments at the antigen receptor loci are repeatedly rearranged to create a vast repertoire of antigen receptor genes. Because V(D)J recombination entails the cleavage and joining of widely dispersed gene segments many millions of times each day, even a miniscule error rate would still carry considerable risk of translocation. Given the deleterious consequences of aberrantly repaired double strand breaks (DSBs), B and T cells tightly regulate V(D)J recombination at three main levels: lineage specificity (e.g., completed rearrangements of B cell loci occur only in B cells and not T cells), ordered rearrangement within a given lineage (e.g., the heavy chain locus in B cells rearranges before the light chain loci), and allelic exclusion (expression of only one functionally rearranged allele on the surface of the cell, thereby ensuring the unique antigen receptor specificity required by the clonal selection theory). The mechanisms underlying these various regulatory constraints are being intensively studied, but many remain stubbornly elusive. My lab has been particularly interested in allelic exclusion and how it might be coordinated with ordered rearrangement within a given lineage. Our most recent work, funded by the parent grant ('Co-ordination of recombination and allelic exclusion at Igh and Igk loci ) has provided some striking insights into these questions. In brief, we discovered that: 1) homologous Ig alleles pair up in a stage-specific manner that parallels the sequential stages of recombination at those loci; 2) STAT5 modulates accessibility of the Ig loci, which in turn affects both interchromosomal and interallelic pairing; 3) interallelic association of Ig loci is mediated by the V(D)J recombinase (i.e., the RAG1 and RAG2 proteins) and the DNA damage checkpoint protein ATM: RAG cleavage on one allele induces repositioning of the other allele to pericentromeric heterochromatin to prevent further cleavage, and this repositioning does not occur in the absence of ATM (Hewitt et al., Nature Immunology, 2009). These findings open up a number of intriguing avenues of study, as do the other observations we have made in pursuit of the aims of the parent grant. We would now like to expand our existing aims to ask what common mechanisms are involved in co-ordinating recombination and allelic exclusion of antigen receptor loci in both B and T cells.This competitive supplement was specifically funded for one of the aims on the application, namely to determine what role Igk/Tcrb association plays in constraining the accessibility of these loci in developing B and T cells. Lineage-specific regulation of recombination is critical for ensuring that the appropriate loci are recombined in the appropriate cell type. We have exciting new data indicating that regulation of the Igk and Tcrb loci is intertwined. We will extend these studies to determine how pairing of the two loci restrains their accessibility within the B and T cell lineage.
Project Description: As defined in the Award Description field.
Infrastructure Description: Not applicable
Jobs Summary: Project not started. (Total jobs reported: 0)
Project Status: Not Started
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