The role of RuvBL2 in the development, maturation, and aging of antibody producing B-cells

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The human body encounters a limitless number of potential foreign antigens on a daily basis. How, then, does our body recognize and fend off such foreign invaders before having had any prior exposure to them? An important component of the immune system are B-cells, which produce high affinity antibodies that are highly specific for a given antigen. Instead of encoding individual genes to produce individual antibodies, B-cells evolved the ability to have one specific gene undergo programmed mutagenesis, which leads to large scale genomic rearrangements combined with an extraordinarily high rate of point mutations, where a single base of the DNA is altered, reaching a million-fold above background levels. Paradoxically, however, the same machinery that normally protects our genome from DNA damage is hijacked by B-cells in order to induce these mutagenic alterations. Therefore, unlike all other somatic cells, B-cells are unique in that their development and maturation is dependent on programmed genomic instability. As one may expect, this mutagenic process sometimes results in off-target mutations at non-antibody genes, which can lead to chromosomal instability and compromises the health and well-being of many organisms. One such example is the accumulation of mutations in B-cells leading to the aging of the immune compartment, which has been acquiring increased emphasis as an important driver for organismal ageing. The aim of my research proposal is to understand how DNA repair processes affect the development, maturation, and ageing of B-cells. Our results will have broad implications for the mechanisms underlying antibody diversification, genomic instability, tumorigenesis, and how DNA damage affects cellular and organismal aging.