Understanding the way in which the immense amount of DNA contained in a eucaryotic nucleus is organized is one of the greatest challenges in molecular biology. This organization must ensure a mechanism for the orderly progress of DNA replication in each cell cycle and for the highly orchestrated expression of specific genes throughout development. One level of organization of the DNA can be described as consisting of topologically constrained domains (loops), each containing approximately 30,000-100,000 base pairs of DNA, anchored to a nuclear skeleton or matrix. Our initial studies have produced several intriguing observations relating the organization of DNA into loops, the nuclear matrix, and the processes of DNA replication and gene expression. In the experiments proposed in this application, we wish to test three hypotheses based on these initial data. These hypotheses are concerned, respectively, with the following ideas: (i) specific sequences within loop domains serve as their anchorage sites; the anchorage sites serve to non-randomly organize the DNA in a nucleus into discrete domains; (ii) transcriptional activation of a loop domain results in a special arrangement of DNA with respect to the structural components at its base; this arrangement of DNA with respect to the structural components at its base; this arrangement is envisaged as part of a structural network mediating the transcription of genes and the processing and transport of the genes' products; (iii) dramatic changes in the loop domains occur during embryonic development; these changes mirror those that occur in replicons. Each of these hypotheses will be rigorously tested using biochemical and morphological techniques developed in our laboratory over the past three years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043460-07
Application #
3185642
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1983-08-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Robles, Ana I; Traverso, Giovanni; Zhang, Ming et al. (2016) Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology 150:931-43
Sur, Surojit; Qiao, Yuan; Fries, Anja et al. (2015) PRINT: A Protein Bioconjugation Method with Exquisite N-terminal Specificity. Sci Rep 5:18363
Wang, Yuxuan; Springer, Simeon; Mulvey, Carolyn L et al. (2015) Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med 7:293ra104
Perica, Karlo; Bieler, Joan Glick; Sch├╝tz, Christian et al. (2015) Enrichment and Expansion with Nanoscale Artificial Antigen Presenting Cells for Adoptive Immunotherapy. ACS Nano 9:6861-71
Skora, Andrew D; Douglass, Jacqueline; Hwang, Michael S et al. (2015) Generation of MANAbodies specific to HLA-restricted epitopes encoded by somatically mutated genes. Proc Natl Acad Sci U S A 112:9967-72
Waclaw, Bartlomiej; Bozic, Ivana; Pittman, Meredith E et al. (2015) A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity. Nature 525:261-4
Echeverria, Ignacia; Liu, Yunlong; Gabelli, Sandra B et al. (2015) Oncogenic mutations weaken the interactions that stabilize the p110?-p85? heterodimer in phosphatidylinositol 3-kinase ?. FEBS J 282:3528-42
Le, Dung T; Uram, Jennifer N; Wang, Hao et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372:2509-20
Ewing, Adam D; Gacita, Anthony; Wood, Laura D et al. (2015) Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res 25:1536-45
Wang, Yuxuan; Springer, Simeon; Zhang, Ming et al. (2015) Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A 112:9704-9

Showing the most recent 10 out of 167 publications