title: H2AX haploinsufficiency modifies genomic stability and tumor susceptibility.
abstract: Histone H2AX becomes phosphorylated in chromatin domains flanking sites of DNA double-strand breakage associated with gamma-irradiation, meiotic recombination, DNA replication, and antigen receptor rearrangements. Here, we show that loss of a single H2AX allele compromises genomic integrity and enhances the susceptibility to cancer in the absence of p53. In comparison with heterozygotes, tumors arise earlier in the H2AX homozygous null background, and H2AX(-/-) p53(-/-) lymphomas harbor an increased frequency of clonal nonreciprocal translocations and amplifications. These include complex rearrangements that juxtapose the c-myc oncogene to antigen receptor loci. Restoration of the H2AX null allele with wild-type H2AX restores genomic stability and radiation resistance, but this effect is abolished by substitution of the conserved serine phosphorylation sites in H2AX with alanine or glutamic acid residues. Our results establish H2AX as genomic caretaker that requires the function of both gene alleles for optimal protection against tumorigenesis.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Arkady
authors.initials: A
authors.lastname: Celeste
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Difilippantonio
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Duane R
authors.initials: DR
authors.lastname: Pilch
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Sedelnikova
authors.affiliation: Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007621:Karyotyping; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004247:DNA; D006657:Histones; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse