myc oncogene-induced genomic instability dna palindromes in bursal lymphomagenesismyc oncogene-induced基因组不稳定性的dna回文囊的便.pdfVIP

Myc Oncogene-Induced Genomic Instability: DNA Palindromes in Bursal Lymphomagenesis 1,2 1 1 1 Paul E. Neiman *, Katrina Elsaesser , Gilbert Loring , Robert Kimmel 1 Divisions of Basic Science, Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Department of Medicine, University of Washington School of Medicine, Seattle Washington, United States of America Abstract Genetic instability plays a key role in the formation of naturally occurring cancer. The formation of long DNA palindromes is a rate-limiting step in gene amplification, a common form of tumor-associated genetic instability. Genome-wide analysis of palindrome formation (GAPF) has detected both extensive palindrome formation and gene amplification, beginning early in tumorigenesis, in an experimental Myc-induced model tumor system in the chicken bursa of Fabricius. We determined that GAPF-detected palindromes are abundant and distributed nonrandomly throughout the genome of bursal lymphoma cells, frequently at preexisting short inverted repeats. By combining GAPF with chromatin immunoprecipitation (ChIP), we found a significant association between occupancy of gene-proximal Myc binding sites and the formation of palindromes. Numbers of palindromic loci correlate with increases in both levels of Myc over-expression and ChIP-detected occupancy of Myc binding sites in bursal cells. However, clonal analysis of chick DF-1 fibroblasts suggests that palindrome formation is a stochastic process occurring in individual cells at a small number of loci relative to much larger numbers of susceptible loci in the cell population and that the induction of palindromes is not involved in Myc-induced acute fibroblast transformat