Replication stress in hematopoiesis and lymphomagenesis

造血和淋巴瘤发生中的复制应激

• 批准号: 10532172
• 负责人: CHRISTINE M. EISCHEN
• 金额: $ 41.94万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532172
• 关键词: Acceleration; Acute; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biological; Biology; Blood Cells; Bone Marrow; Bone marrow failure; CD34 gene; Cells; Cellular Stress; Cessation of life; Chronic; Critical Pathways; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA replication fork; Data; Defect; Development; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Growth; Heat shock proteins; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Immunologic Deficiency Syndromes; In Vitro; Knockout Mice; Link; Lymphoma; Lymphoma cell; Lymphomagenesis; MYC gene; Malignant Neoplasms; Mediating; Methods; Mus; Myelogenous; Oncogenes; Pathology; Pathway interactions; Physiological; Predisposition; Process; Proteins; Radiation; Reporting; Resolution; Role; Single-Stranded DNA; Stimulus; Stress; T-Cell Development; T-Cell Lymphoma; T-Lymphocyte; Techniques; Testing; Therapeutic Intervention; biological adaptation to stress; exhaustion; genetic approach; genome integrity; genome-wide; improved; in vivo; in vivo evaluation; innovation; insight; loss of function; mouse model; replication stress; self-renewal; stem; stem cells; tumor; tumorigenesis

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.

概括 造血系统对引起DNA复制应力的刺激特别敏感， 这可能导致DNA断裂。正确应对这种压力的能力的缺陷是 与血液学恶性肿瘤，造血细胞缺陷和 骨髓衰竭。最近的进步包括鉴定对DNA反应的基因 复制应力和对特异性造血所必需的基因的更多了解 血统，但对这两个过程以及它们如何相交的造成 病理。此外，在人类癌症中观察到DNA复制应力，由 癌基因（例如Myc）会造成DNA损伤并导致基因组不稳定性，但它 仍然很了解。 SMARCAL1以及最近，识别并评估了Zranb3 生化和体外研究以本地化为复制叉，对于响应至关重要 达到DNA复制应力。 smarcal1和zranb3是叉子重塑，反向复制 叉子可以修复受损的DNA和倒带单链DNA。两者都smarcal1和 Zranb3具有相似的功能，但报道了生化差异。但是，功能 Zranb3和smarcal1以及它们是多余的还是互补的 尚未探索复制应力或在体内具有独特的功能。最近，我们 从遗传上证明smarcal1对于介导急性DNA的作用至关重要 对造血干细胞和祖细胞的复制应力，并有助于 T细胞淋巴瘤的发展。我们的初步数据支持Zranb3的假设 以不同于Smarcal1的方式有助于造血和淋巴作用 Zranb3和Smarcal1共同有助于造血和淋巴瘤发育。 因此，我们提出了三个目的，其中具有体内遗传方法来检验该假设。 1） 研究Zranb3在MYC诱导的复制应力中的作用及其对急性的贡献 慢性复制应激诱导的淋巴瘤发育。 2）确定Zranb3在 造血和造血干和祖细胞复制应激。 3）评估 Zranb3和smarcal1在造血和淋巴瘤发生中的功能的综合丧失。 通过新的鼠标模型和多种方法对创新概念进行了测试，包括 高分辨率基因组广泛的终端。这些目标的完成将大大 提前了解DNA复制应激蛋白及其对基因组的贡献 稳定性，造血和血液学恶性肿瘤。

项目成果

Mdm4 supports DNA replication in a p53-independent fashion.

• DOI: 10.1038/s41388-020-1325-1
• 发表时间: 2020-06
• 期刊: Oncogene
• 影响因子: 8
• 作者: Wohlberedt K;Klusmann I;Derevyanko PK;Henningsen K;Choo JAMY;Manzini V;Magerhans A;Giansanti C;Eischen CM;Jochemsen AG;Dobbelstein M
• 通讯作者: Dobbelstein M