title: Histone modifications predispose genome regions to breakage and translocation.
abstract: Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we identify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; Program in Cell, Molecular, and Developmental Biology, Tufts University Sackler School of Biomedical Sciences, Boston, Massachusetts 02111, USA;
authors.forename: Bharat
authors.initials: B
authors.lastname: Burman
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
authors.forename: Zhuzhu Z
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pegoraro
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D045744:Cell Line, Tumor; D019457:Chromosome Breakage; D019295:Computational Biology; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004720:Endonucleases / Q000378:metabolism; D015894:Genome, Human / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000503:physiopathology; D008745:Methylation; D014178:Translocation, Genetic
chemical_list: D006657:Histones; D004720:Endonucleases
keywords: chromatin structure; chromosome translocations; histone modifications