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

人体每天都会遇到无限数量的潜在外来抗原。那么，在事先接触到这些外来入侵者之前，我们的身体是如何识别和抵御它们的呢？免疫系统的一个重要组成部分是B细胞，它能产生对特定抗原高度特异的高亲和力抗体。B细胞没有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经历程序性突变的能力，这导致了大规模的基因组重排和极高的点突变比率，即DNA的一个碱基发生改变，达到背景水平的100万倍。然而，矛盾的是，通常保护我们的基因组免受DNA损伤的相同机制却被B细胞劫持，以诱导这些突变改变。因此，与所有其他体细胞不同，B细胞的发育和成熟依赖于程序性基因组的不稳定性，这一点是独特的。正如人们可能预料的那样，这种突变过程有时会导致非抗体基因的非靶标突变，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。一个这样的例子是B细胞中突变的积累导致免疫隔间的老化，免疫隔间作为生物体老化的重要驱动因素得到了越来越多的重视。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、成熟和老化。我们的结果将对抗体多样化、基因组不稳定、肿瘤发生的潜在机制以及DNA损伤如何影响细胞和生物衰老具有广泛的意义。

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.