H2AX haploinsufficiency modifies genomic stability and tumor susceptibility
H2AX haploinsufficiency modifies genomic stability and tumor susceptibility
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DOI：
10.1016/s0092-8674(03)00567-1
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发表时间：
2003-08-08
期刊：
影响因子：
64.5
通讯作者：
Nussenzweig, A
中科院分区：
文献类型：
--
作者：
Celeste, A;Difilippantonio, S;Nussenzweig, A
组蛋白H2 AX在与γ-辐射、减数分裂重组、DNA复制和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磷酸化。在这里，我们表明，一个单一的H2 AX等位基因的损失损害基因组的完整性，并提高了癌症的易感性，在没有p53。与杂合子相比，肿瘤在H2 AX纯合无效背景下出现更早，H2 AX（-/-）p53（-/-）淋巴瘤具有增加的克隆性非相互易位和扩增频率。这些包括将c-myc癌基因与抗原受体位点并列的复杂重排。用野生型H2 AX恢复H2 AX无效等位基因可恢复基因组稳定性和辐射抗性，但通过用丙氨酸或谷氨酸残基取代H2 AX中的保守丝氨酸磷酸化位点可消除这种作用。我们的研究结果确立了H2 AX作为基因组看护者，需要两个基因等位基因的功能以最佳地保护免受肿瘤发生。
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.