Replication stress in hematopoiesis and lymphomagenesis

总结 造血系统对引起DNA复制应激的刺激特别敏感， 这会导致DNA断裂对这种压力作出适当反应的能力缺陷是 与血液系统恶性肿瘤、造血细胞缺陷的易感性有关， 骨髓衰竭最新进展包括识别对DNA做出反应的基因 复制压力和更深入地了解特定造血细胞的造血所需的基因， 血统，但仍有很多关于这两个过程以及它们如何交叉导致 病理此外，在人类癌症中观察到DNA复制应激， 癌基因如Myc，引起DNA损伤，并导致基因组不稳定，但它 仍然知之甚少。Smarcal 1和最近的Zranb 3被鉴定和评估 通过生物化学和体外研究，定位于复制叉， DNA复制压力。Smarcal 1和Zranb 3是分叉重塑和反向复制 分叉，以修复受损的DNA和倒带单链DNA。Smarcal 1和 Zranb 3具有类似的功能，但报道了生化差异。然而，功能 的Zranb 3和Smarcal 1，以及它们是否是冗余或互补的时候， 复制应力或在体内具有独特功能尚未探索。最近我们 遗传学上证明Smarcal 1对于介导急性DNA损伤的作用是必不可少的。 复制应激对造血干细胞和祖细胞，并有助于 T细胞淋巴瘤的发展。我们的初步数据支持这一假设， 以不同于Smarcal 1的方式促进造血和淋巴瘤生成， Zranb3和Smarcal 1共同促进造血和淋巴瘤的发展。 因此，我们提出了三个目标与体内遗传学的方法来验证这一假设。第一章 研究Zranb 3在Myc诱导的复制应激中的作用及其在急性和慢性炎症中的作用。 慢性复制应激诱发淋巴瘤发展。2)确定Zranb3在 造血和造血干细胞和祖细胞复制应激。3)评价 在造血和淋巴瘤发生中Zranb 3和Smarcal 1的功能的联合丧失。 创新概念通过新的小鼠模型和多种方法进行测试，包括 高分辨率全基因组末端测序。这些目标的实现将大大 深入了解DNA复制应激蛋白及其对基因组的贡献 稳定性、造血和血液恶性肿瘤。

Summary The hematopoietic system is particularly sensitive to stimuli that cause DNA replication stress, which can result in DNA breaks. Defects in the ability to properly respond to this stress are linked to a predisposition to hematologic malignancies, hematopoietic cell deficiencies, and bone marrow failure. Recent advances include the identification of genes that respond to DNA replication stress and a greater understanding of genes necessary for hematopoiesis of specific lineages, but much remains unknown about both processes and how they intersect to cause pathology. Moreover, DNA replication stress is observed in human cancers, is induced by oncogenes such as Myc, causes DNA damage, and contributes to genome instability, but it remains poorly understood. Smarcal1 and more recently, Zranb3 were identified and evaluated biochemically and by in vitro studies to localize to replication forks and be critical for responding to DNA replication stress. Smarcal1 and Zranb3 are fork remodelers and reverse replication forks to allow repair of damaged DNA and rewind single-stranded DNA. Both Smarcal1 and Zranb3 have similar functions, but biochemical differences are reported. However, the functions of Zranb3 and Smarcal1 and whether they are redundant or complementary at times of replication stress or have unique functions in vivo has not been explored. Recently, we genetically demonstrated that Smarcal1 was essential for mediating the effects of acute DNA replication stress on hematopoietic stem and progenitor cells and contributed to the development of T cell lymphoma. Our preliminary data support the hypothesis that Zranb3 contributes to hematopoiesis and lymphomagenesis in ways distinct from Smarcal1, and that Zranb3 and Smarcal1 together contribute to hematopoiesis and lymphoma development. Therefore, we propose three Aims with in vivo genetic approaches to test this hypothesis. 1) Investigate the role of Zranb3 in Myc-induced replication stress and its contribution to acute and chronic replication stress-induced lymphoma development. 2) Determine the role of Zranb3 in hematopoiesis and hematopoietic stem and progenitor cell replication stress. 3) Evaluate the combined loss of function of Zranb3 and Smarcal1 in hematopoiesis and lymphomagenesis. Innovative concepts are tested with a new mouse model and multiple approaches, including high-resolution genome wide end-sequencing. Completion of these Aims will significantly advance understanding into DNA replication stress proteins and their contribution to genome stability, hematopoiesis, and hematological malignancies.