The ability to generate immune systems that discriminate between self and foreign antigens is vital for the life, health, and reproduction of all mammalian species. Starting in utero, mammals develop distinct lymphocyte lineages that segregate into innate and adaptive arms of immune systems. Innate lymphocytes express invariant germline-encoded antigen receptors, while adaptive lymphocytes express diverse antigen receptors somatically-assembled from germline variable, diversity, and joining gene segments.
The RAG1/RAG2 (RAG) endonuclease-mediated assembly of Ig and TCR genes in immature B and T lymphocytes, respectively, is essential for the development and function of adaptive immunity. However, this process confers fatal risk as evidenced by generation of auto-reactive receptors and lymphoid malignancies with oncogenic Ig/TCR translocations. Immature B and T cells share developmental strategies that include mono-allelic gene recombination and feedback mechanisms, which link protein expression from functional V(D)J rearrangements to further developmental progression or negative selection of auto-reactive cells. The genetic, epigenetic, and biochemical mechanisms governing these facets of lymphocyte differentiation remain largely unknown. RAG DNA double strand breaks (DSBs) engage conserved cellular DNA damage responses to inhibit the formation and oncogenic potential of aberrant genomic rearrangements.
The Bassing Lab has discovered that RAG DSBs activate tissue-specific DNA damage responses and transcend hazardous intermediates during antigen receptor gene assembly. RAG cleavage in the genomes of lymphocyte progenitors and immature lymphocytes regulates the expression of ubiquitous and lymphocyte-specific gene transcripts to control the differentiation and function of both adaptive and innate lymphocyte lineages. The lab has also demonstrated the RAG1 ubiquitin ligase signals from RAG DSBs to post-transcriptionally shape proteomes of immature lymphocyte to drive development of B and T cell subtypes and facilitate proper negative selection of strongly auto-reactive cells. These discoveries raise important novel questions that have broad-ranging implications for basic immunology research and the screening, diagnosis, and treatment of human immunological disease.
- Elucidate How Genome Topology Regulates Transcription and Recombination
- Determine Mechanisms and Physiological Roles of Allelic Exclusion
- Elucidate Mechanisms and Functions of DSB Feedback Inhibition of V(D)J Recombination
- Determine Mechanisms and Roles of RAG1 Post-Transcriptional Control of Gene Expression
- Elucidate Mechanisms and Functions of Tissue-, Lineage-, and Developmental-Stage Specific DNA Damage Responses of Immature Lymphocytes