Weakened spindle checkpoint in vivo: a cause of aneuploidy and cancer in FA?

体内纺锤体检查点减弱：FA 中非整倍体和癌症的原因？

• 批准号: 9191387
• 负责人: DONNA EDWARDS
• 金额: $ 2.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-13 至 2018-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191387
• 关键词: Accounting; Acute Myelocytic Leukemia; Acute leukemia; Address; Affect; Anaphase; Aneuploidy; Animals; BRCA2 gene; Binding; Bone Marrow Cells; CDC2 Protein Kinase; Cancer Etiology; Cells; Centrosome; Chromosome Segregation; Complex; DNA Repair; DNA biosynthesis; Data; Development; Dysmyelopoietic Syndromes; Ensure; Family; Fanconi Anemia pathway; Fanconi Anemia-BRCA Pathway; Fanconi anemia protein; Fanconi' s Anemia; Functional disorder; Future; General Population; Genes; Genome; Genome Stability; Genomic Instability; Germ-Line Mutation; Hereditary Disease; Heterozygote; High-Risk Cancer; Housekeeping; Impairment; Inherited; Interphase; Laboratories; Lead; MXI1 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Metaphase; Micronucleus Tests; Mitosis; Mitotic; Mitotic Checkpoint; Mitotic spindle; Modeling; Mus; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Predisposition; Proteins; Research; Risk; Role; Secondary to; Signal Transduction; Somatic Mutation; Syndrome; Testing; Therapeutic; Tumor Suppressor Proteins; Work; base; cancer therapy; clinically relevant; clinically significant; genome integrity; in vivo; malignant breast neoplasm; mouse model; novel; novel therapeutics; pre-clinical; preclinical study; prevent; repaired; targeted treatment; treatment strategy; tumor; tumorigenesis

PROJECT SUMMARY Fanconi anemia (FA/BRCA) pathway is comprised of at least 17 proteins that maintain genomic stability and prevent cancer. Bi-allelic germline disruption of any FA gene causes Fanconi anemia (FA), a genetic disorder causing bone marrow failure and high risk of cancer. Somatic mutations of FA/BRCA genes occur in spontaneous cancers. Thus, disruption of FA/BRCA signaling promotes malignancies in both inherited syndromes and the general population. The FA tumor suppressor network controls multiple genome-housekeeping checkpoints. In addition to the well-established roles of FA proteins in interphase DNA replication/repair, the FA pathway controls mitosis, including the spindle assembly checkpoint (SAC), a tumor suppressor network that regulates chromosome segregation. The SAC is regulated by several tumor suppressors, including MAD2, and SAC impairment predisposes to aneuploidy and cancer. However, the mechanisms causing abnormal SAC function upon loss of FA remain largely unknown. Furthermore, the in vivo clinical significance of SAC dysfunction in the pathogenesis of FA-associated cancers needs to be explored before the development of future therapeutic strategies targeting the weakened SAC in FA-deficient cells can become a reality. We hypothesize that SAC dysfunction contributes to the in vivo development of aneuploidy and cancer upon loss of FA signaling. To test this hypothesis, we have generated a novel Fancc-/-; Mad2+/- mouse model, in which Mad2 heterozygosity further weakens SAC function in the FA-deficient background. In Aim 1, we will determine whether these Fancc-/-; Mad2+/- mice are cancer-prone. Utilizing cells from these animals, we will employ a micronucleus test to assess the relative contribution of SAC dysfunction to the development of aneuploidy in comparison to other known factors such as interphase DNA damage repair. Additionally, we aim to dissect the mechanism by which loss of FANCC contributes to erroneous chromosome segregation and impaired mitosis by defining the relationship between FANCC and its binding partner CDK1, a well-known regulator of the metaphase-to-anaphase transition (Aim 2). This proposal will lead to a better understanding of SAC dysfunction as a driver of genomic instability and tumorigenesis in the context of FA signaling inactivation, and ultimately contribute to the development of mitotic-centered therapies for FA-associated tumors.

项目摘要 Fanconi贫血（FA/BRCA）通路由至少17种维持基因组稳定性的蛋白质组成 预防癌症。任何FA基因的双等位基因生殖系破坏都会导致范可尼贫血（FA），这是一种遗传性贫血。 导致骨髓衰竭和癌症高风险的疾病。FA/BRCA基因的体细胞突变发生在 自发性癌症因此，FA/BRCA信号传导的破坏促进了两种遗传性肿瘤中的恶性肿瘤。 综合征和一般人群。 FA肿瘤抑制网络控制多个基因组管家检查点。除了 FA蛋白在间期DNA复制/修复中的公认作用，FA途径控制有丝分裂， 包括纺锤体组装检查点（SAC），一种调节染色体的肿瘤抑制网络， 种族隔离SAC受几种肿瘤抑制因子调节，包括MAD 2和SAC损伤 易患非整倍体和癌症然而，在丧失时引起SAC功能异常的机制 FA在很大程度上仍然未知。此外，SAC功能障碍在体内的临床意义， FA相关癌症的发病机制需要在开发未来的治疗药物之前进行探索。 靶向FA缺陷细胞中的弱化SAC的策略可以成为现实。 我们假设SAC功能障碍有助于体内非整倍体和癌症的发展 在FA信号丢失时。为了检验这一假设，我们已经产生了一种新的Fancc-/-; Mad 2 +/-小鼠模型， 其中Mad 2杂合性进一步削弱了FA缺陷背景下的SAC功能。在目标1中，我们 确定这些Fancc-/-; Mad 2 +/-小鼠是否具有癌症倾向。利用这些动物的细胞， 采用微核试验来评估SAC功能障碍对疾病发展的相对贡献 与其他已知的因素如间期DNA损伤修复相比，非整倍性是非常重要的。此外，我们旨在 剖析FANCC缺失导致染色体错误分离的机制， 通过定义FANCC与其结合伴侣CDK 1之间的关系， 中期到后期过渡的调节剂（目的2）。这一建议将有助于更好地了解 SAC功能障碍是FA信号失活背景下基因组不稳定性和肿瘤发生的驱动因素， 并最终有助于FA相关肿瘤的有丝分裂中心疗法的发展。