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Cellular Responses to Cancer Drug-Induced Genomic Breaks

细胞对癌症药物引起的基因组断裂的反应

基本信息

批准号：
7331469
负责人：
TERRY A BEERMAN
金额：
$ 27.65万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-14 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7331469
关键词：
1-Phosphatidylinositol 3-Kinase Antineoplastic Agents Ataxia-Telangiectasia-Mutated protein kinase C 1027 Cell Cycle Checkpoint Cell Cycle Progression Cells Characteristics Chromosome abnormality Chromosomes Chromosomes, Human, Pair 3 Condition Cytogenetic Analysis DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA-Binding Proteins Disruption Ensure Fluorescent in Situ Hybridization Functional disorder Genetic Recombination Genomics Immunofluorescence Microscopy Interphase Ionizing radiation Ku Protein Measures Metaphase Mitosis Mitotic Modeling Nonhomologous DNA End Joining Oligonucleotides Pathway interactions Pharmaceutical Preparations Phosphotransferases Play Process Property Proteins Regulation Role Spectral Karyotyping Tandem Repeat Sequences Testing Western Blotting antitumor drug cytotoxic homologous recombination insight repaired response telomere

项目摘要

DESCRIPTION (provided by applicant): Cellular responses to ionizing radiation (IR)-induced DNA double strand breaks (DSBs) involve activation, via the phosphatidylinositol 3-kinase-like kinase (PIKK) ATM, of cell cycle checkpoint proteins that delay cell cycle progression to allow DNA repair and to preserve chromosomal integrity. Responses to DNA DSBs induced by the radiomimetic enediyne C-1027 deviate from this model. For example, IR induces ATM-dependent, and C-1027, both ATM- dependent and independent, responses. Furthermore, treatment with equi-cytotoxic levels of IR or C-1027 results in either a very low (2.9%), or an extraordinarily high (92%), percentage, respectively of mitotic cells showing aberrant chromosomal recombination. FISH analysis revealed that C-1027-induced chromosomal aberrations are frequently associated with disruption of telomeres. The mechanism(s) behind these unique responses to the antitumor drug, C-1027 should help extend our understanding of DNA damage responses to DSBs. First, pivotal checkpoint pathway proteins involved in the response to C-1027 will be identified, with emphasis on both ATM-dependent and independent responses. Next the conditions under which C-1027 induces extensive chromosomal fusions, characterized by aberrant end-joining and fragmentation, will be identified. The NHEJ DNA binding protein Ku, which not only is involved in repair responses but also plays a role in regulating chromosomal fusions, will also be examined for its role in C-1027 induced aberrant end-joining. Finally, we will test whether C-1027, which induces DSBs preferentially within a GTTA motif, targets the telomere tandem repeat sequence (GGGTTA) and contributes to aberrant end-joining by inducing telomere dysfunction. Other enediynes with cleavage characteristics different from C-1027, will be tested selectively to provide additional mechanistic insights into which properties of C-1027-induced damage are associated with the DNA damage responses. The specific aims will test the following hypotheses: 1. C-1027 is unique compared to other enediynes and to IR in that it induces both ATM-dependent and independent DNA damage responses. 2. C-1027 is unique compared to other enediynes and to IR in that it causes extraordinarily high levels of rearranged chromosomes. 3. C-1027 is unique compared to other enediynes and IR in that it targets telomeres.

描述(申请人提供)：细胞对电离辐射(IR)诱导的DNA双链断裂(DSB)的反应涉及通过磷脂酰肌醇3-激酶样激酶(Pikk)ATM激活细胞周期检查点蛋白，该蛋白可以推迟细胞周期进程，以实现DNA修复和保持染色体的完整性。模拟辐射的烯二炔C-1027对DNA双链断裂的反应偏离了这一模型。例如，IR诱导ATM依赖和C-1027两种依赖于ATM和独立的响应。此外，用等细胞毒性水平的IR或C-1027处理后，有丝分裂细胞出现异常染色体重组的比例分别为非常低(2.9%)和极高(92%)。FISH分析表明，C-1027诱导的染色体异常经常与端粒的破坏有关。抗肿瘤药物C-1027的这些独特反应背后的机制(S)应该有助于扩大我们对DSB的DNA损伤反应的理解。首先，将确定与C-1027反应有关的关键检查点途径蛋白，重点是ATM依赖和独立反应。接下来，将确定C-1027诱导广泛的染色体融合的条件，其特征是异常的末端连接和碎裂。NHEJ DNA结合蛋白Ku不仅参与修复反应，而且在调节染色体融合方面发挥作用，也将研究其在C-1027诱导的异常末端连接中的作用。最后，我们将测试C-1027是否以端粒串联重复序列(GGGTTA)为靶点，通过诱导端粒功能障碍而导致端粒功能障碍，从而优先诱导GTTA基序中的DSB。其他具有不同于C-1027的切割特征的烯二炔将被选择性地测试，以提供更多关于C-1027诱导的损伤的性质与DNA损伤反应相关的机制见解。具体目标将检验以下假设： 1.C-1027与其他烯二炔类化合物和IR相比是独特的，因为它既能诱导ATM依赖的DNA损伤反应，也能诱导独立的DNA损伤反应。 2.与其他烯二炔类化合物和IR相比，C-1027的独特之处在于它能引起极高水平的染色体重排。 3.C-1027与其他烯二炔和IR相比是独特的，因为它以端粒为靶点。