DNA STRAND BREAKS AND THE GENETIC BASIS OF LYMPHOMAS

DNA 链断裂和淋巴瘤的遗传基础

• 批准号: 6376671
• 负责人: GILBERT CHU
• 金额: $ 22.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-12 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376671
• 关键词: DNA damage; DNA topoisomerases; ataxia telangiectasia; biopsy; cancer risk; enzyme activity; enzyme inhibitors; gene mutation; high performance liquid chromatography; human tissue; lymphoma; neoplasm /cancer genetics; neoplastic process; pathologic process; protein kinase; radiation resistance; tumor suppressor genes; western blottings

Mammalian cells respond to DNA double-strand breaks (DSBs) by activating pathways for cell cycle arrest and DNA repair. The signal for cell cycle arrest requires the ATM and p53 genes, which are mutated in at ataxia telangiectasia and Li-Fraumeni syndrome. DSB repair requires four genes: XRCC4, XRCC5 (Ku86), XRCC6 (Ku70), and XRCC7 (DNA-PKcs, the catalytic subunit of DNA-dependent protein kinase), the latter of which is mutated in the scid mouse. Ataxia telangiectasia and Li-Fraumeni patients and the scid mouse are highly susceptible to lymphoma. Thus, a small fraction of lymphomas must arise from germ line mutations in one of the DSB response genes. This proposal will test the hypothesis that a significant fraction arises from somatic mutations in these genes. The specific aims are to: 1.1. Test lymphoma tumors for biochemical abnormalities in pathways responding to DSBs. Lymphomas will be screened for biochemical abnormalities in the known DSB response genes. The assays are rapid and sensitive to mutations in these and other genes in the DSB response pathway. The assays will test DNA end-binding activity for Ku, assembly of DNA-PK on DNA ends and its enzymatic activity. Immunoblots will evaluate the Ku, DNA-PKcs, p53, and ATM proteins, which are often altered in stability of size by mutations. 1.2. Test lymphoma tumors for genetic abnormalities in pathways responding to DSBs. Lymphoma tumors will be tested for mutations in the DSB response genes. The hunt for mutations will be facilitated by new technology, which consists of denaturing high performance liquid chromatography and is capable of detecting mutations with greater than 98 percent sensitivity much more rapidly than conventional methods. 1.3. Correlate abnormalities in pathways responding to DSBs with clinical and other lab findings. Surprisingly, most diffuse lymphomas utilize the VH4.21 immunoglobulin gene. Since ATM mutations lead to aberrant V(D)J recombination, this proposal will test if they also lead to biased VH4.21 usage. Since many lymphomas do not have p53 mutations, this proposal will test whether the remaining lymphomas have mutations in ATM, which acts in the same signaling pathway. Since DSB response genes confer resistance to key anticancer agents, this proposal will test whether mutations in these genes affect clinical outcome. The long term goal is to define the genetic changes that mediate malignant progression of lymphomas. Hopefully, molecular analysis of individual lymphomas will some day lead to the cure of more patients.

哺乳动物细胞对DNA双链断裂（DSBs）的反应是激活

项目成果

Contributions of ATM mutations to familial breast and ovarian cancer.

• 发表时间: 2003-06
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Y. Thorstenson;Adriane Roxas;R. Kroiss;M. Jenkins;Kristine M. Yu;T. Bachrich;D. Muhr;T. Wayne;G. Chu;Ronald W. Davis;T. Wagner;P. Oefner