Developing lymphocytes transcriptionally regulate non-homologous end joining genes concurrent with V(D)J recombination

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B1023
Abstract ID: 5724

Presenting Author:
Patrick L Collins , Assistant Professor at Ohio State Univ. Col. of Med.

Abstract:

Our immune system depends upon precisely controlled cycles of programmed mutagenesis within the antigen receptor (Agr) loci of developing lymphocytes, which produces T and B cell receptor genes. The first step in creating Agr genes is known as V(D)J recombination, wherein RAG complexes induce double strand breaks (DSBs) that delete or flip intervening antigen gene segments. However, error-prone repair is needed to create sequence complexity during junctional diversity, and thus there is a strict requirement for conventional non-homologous end joining (c-NHEJ) for healthy DSB resolution.

Given the critical importance to immune development, we sought to understand the genetic and epigenetic regulation of c-NHEJ repair genes in developing lymphocytes. Our study identifies cis-regulatory genomic elements that govern c-NHEJ genes like Ligase IV (Lig4), which is the final ligase absolutely required for adaptive immune development. Preliminary data from mouse models suggest developing lymphocyte upregulate LIG4 in preparation for the complicated DSBs that occur during V(D)J recombination, and to safeguard progenitor lymphocytes against having multiple breaks at once during times of exogenous damage.  Thus, we predict there are transcriptional mechanisms that promote c-NHEJ in select tissues, which influence repair biology in a cell-type selective way.