Celeste Arkady, Difilippantonio Simone, Difilippantonio Michael J, Fernandez-Capetillo Oscar, Pilch Duane R, Sedelnikova Olga A, Eckhaus Michael, Ried Thomas, Bonner William M, Nussenzweig André
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cell. 2003 Aug 8;114(3):371-383. doi: 10.1016/s0092-8674(03)00567-1.
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.
组蛋白H2AX在与γ射线照射、减数分裂重组、DNA复制及抗原受体重排相关的DNA双链断裂位点侧翼的染色质结构域中发生磷酸化。在此，我们表明，在缺乏p53的情况下，单个H2AX等位基因的缺失会损害基因组完整性并增加患癌易感性。与杂合子相比，肿瘤在H2AX纯合无效背景中出现得更早，且H2AX(-/-) p53(-/-)淋巴瘤中克隆性非相互易位和扩增的频率增加。这些包括使c-myc癌基因与抗原受体基因座并列的复杂重排。用野生型H2AX恢复H2AX无效等位基因可恢复基因组稳定性和抗辐射性，但将H2AX中保守的丝氨酸磷酸化位点替换为丙氨酸或谷氨酸残基会消除这种效应。我们的结果确立了H2AX作为基因组守护者的地位，它需要两个基因等位基因的功能来实现对肿瘤发生的最佳保护。
