Epigenetics of Chromosomal Breakage Sites and Translocations

Friday, November 08, 2013 — Poster Session III
10:00 a.m. – 12:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NCI	CHROM-1

Authors

B Burman
R.C. Burgess
Z Zhang
J.D. Lieb
T Misteli

Abstract

Chromosomal translocations are genetic hallmarks of most cancer cells. There is increasing evidence that translocations occur at non-random sites in the genome, suggesting that certain regions of the genome are more susceptible to DNA breakage than others. We hypothesize that altered chromatin structure predisposes genomic sites to DNA breakage and translocations. To identify chromatin features that facilitate translocations, we have mapped histone modifications and chromatin structure at translocation-prone regions in anaplastic large cell lymphoma (ALCL) precursor cells. We find enrichment of active histone marks and a decrease in repressive marks near frequent translocation breakpoints. In order to directly test the role of chromatin features in DNA breakage susceptibility, we have developed a protein-DNA tethering system that allows us to create local chromatin domains at pre-defined sites in the genome containing inducible DSB sites in vivo. By measuring the amount of DSBs using ligation-mediated PCR, we find that histone modifying enzymes that create active chromatin marks generally increase breakage susceptibility. Taken together, these experiments are providing first insights into the role of chromatin structure in the formation of nonrandom chromosomal breaks and the mechanisms that lead to clinically relevant translocations.