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

人体每天都会接触到无数潜在的外来抗原。那么，我们的身体是如何在事先接触这些外来入侵者之前识别并抵御它们的呢？免疫系统的一个重要组成部分是b细胞，它产生对特定抗原高度特异性的高亲和力抗体。b细胞不再编码单个基因来产生单个抗体，而是进化出了让一个特定基因进行程序性诱变的能力，这导致大规模的基因组重排，并伴随着异常高的点突变率，即DNA的单个碱基被改变，达到背景水平的一百万倍。然而，矛盾的是，通常保护我们基因组免受DNA损伤的相同机制被b细胞劫持，以诱导这些诱变。因此，与所有其他体细胞不同，b细胞的独特之处在于它们的发育和成熟依赖于程序性基因组不稳定性。正如人们所预料的那样，这种诱变过程有时会导致非抗体基因的脱靶突变，这可能导致染色体不稳定并危及许多生物体的健康和福祉。其中一个例子是b细胞中突变的积累导致免疫室的衰老，这已经越来越多地被强调为生物体衰老的重要驱动因素。我的研究计划的目的是了解DNA修复过程如何影响b细胞的发育、成熟和衰老。我们的研究结果将对抗体多样化、基因组不稳定性、肿瘤发生以及DNA损伤如何影响细胞和组织衰老的机制产生广泛的影响。

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.