MYSM1-dependent DNA damage responses in early B cell development

项目总结 先天性免疫错误提供了独特的机会来研究已识别的基因在 免疫系统的发展和功能。对这些免疫紊乱的研究提供了 对人类免疫的重要见解，并建立了基本和临床的基本原则 免疫学。在这一点上，MYSM1的生殖系变异最近被发现存在于原发性心脏病患者中。 免疫缺陷的特征是T细胞减少，B细胞几乎完全消失，低丙种球蛋白血症， 并增加了对基因毒性药物的敏感性。MYSM1在免疫发育和细胞内的作用 对DNA损伤的反应仍然是一个关键的知识缺口。MYSM1基因缺失导致DNA增加 在没有接触DNA损伤剂的情况下，损伤信号，特别是B细胞。在早期 在发育过程中，B细胞(和T细胞)产生DNA断裂，以组装编码其抗体的基因 感受器。这些DNA断裂对于创造免疫系统的多样性至关重要，以识别不同的 病原体。在初步实验中，我们发现，作为对这些程序性DNA断裂的反应， MYSM1导致持续的DNA损伤信号，包括激活细胞死亡程序，从而损害 B细胞成熟。我们的目标是确定MYSM1调节细胞反应的机制 DNA损伤和B细胞发育的协调性。我们建议MYSM1的功能是终止 DNA断裂修复后的DNA损伤反应以及这种活性对抑制细胞死亡至关重要 促进B细胞持续发育的途径。我们将确定MYSM1在DNA损伤信号中的作用 并将确定调节MYSM1活性的机制。理解这些信号 免疫细胞中的直接DNA损伤程序是阐明初级免疫机制的关键 在这方面，我们将继续努力，以弥补不足，并优化治疗方法。这些研究将建立灭活的新范式 DNA损伤反应，并将揭示新的机会，以改善患者的临床管理 MYSM1缺乏以及其他DNA损伤途径异常的患者。

PROJECT SUMMARY Inborn errors of immunity provide unique opportunities to investigate the role of identified genes in the development and function of the immune system. Investigation of these immune disorders has provided important insights into human immunity and has established fundamental principles of basic and clinical immunology. In this regard, germline variants in MYSM1 have recently been identified in patients with primary immune deficiency characterized by low T cells, near complete absence of B cells, hypogammaglobulinemia, and increased sensitivity to genotoxic agents. The role of MYSM1 in immune development and in cellular response to DNA damage remain a critical knowledge gap. Deficiency of MYSM1 results in increased DNA damage signals, particularly in B cells, in the absence of exposure to DNA damaging agents. During early development, B cells (and T cells) generate DNA breaks to assembly the genes that encode their antibody receptors. These DNA breaks are essential for creating the diversity of the immune system to recognize various pathogens. In preliminary experiments, we find that, in response to these programmed DNA breaks, loss of MYSM1 results in persistent DNA damage signaling, including activation of cell death programs, which impairs B cell maturation. Our goal is to determine the mechanism of MYSM1 in regulation of cellular responses to DNA damage and in coordination of B cell development. We propose that MYSM1 functions to terminate DNA damage responses after DNA break repair and that this activity is critical for suppressing cell death pathways to promote continued B cell development. We will define the role of MYSM1 in DNA damage signaling in early B cells and will determine the mechanisms that regulate MYSM1 activity. Understanding the signals that direct DNA damage programs in immune cells is essential for elucidating mechanisms of primary immune deficiency and for optimizing treatment approaches. These studies will establish a new paradigm for inactivating DNA damage responses and will reveal new opportunities to improve clinical management of patients with MYSM1 deficiency as well as patients with abnormalities in other DNA damage pathways.