Histone H2AX: A dosage-dependent suppressor of oncogenic translocations and tumors
Histone H2AX: A dosage-dependent suppressor of oncogenic translocations and tumors
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DOI：
10.1016/s0092-8674(03)00566-x
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发表时间：
2003-08-08
期刊：
影响因子：
64.5
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Bassing, CH;Suh, H;Alt, FW
我们采用基因打靶来研究 H2AX，这是一种在 DNA 双链断裂周围的染色质中磷酸化的组蛋白变体。 H2AX 和 p53 ((HP-/-)-P-Delta/Delta) 缺陷的小鼠迅速发展为未成熟的 T 和 B 淋巴瘤和实体瘤。此外，H2AX 单倍体不足会导致正常细胞中的基因组不稳定，并且在 p53 缺陷的背景下，导致各种肿瘤（包括更成熟的 B 淋巴瘤）的早期发作。大多数 H2AX(Delta/Delta)p53(-/-) 或 H2AX(+/Delta) p53(-/-) B 谱系淋巴瘤携带 12 号染色体 (IgH)/15 (c-myc) 易位，具有异常 V(D)J 或类别转换重组的标志。相比之下，H2AX(Delta/Delta)p53(-/-)胸腺淋巴瘤具有不涉及抗原受体基因座的克隆易位，并且可能发生在细胞扩张期间。因此，H2AX 有助于防止程序性 DNA 断裂和一般性 DNA 断裂的异常修复，从而作为小鼠基因组不稳定性和肿瘤的剂量依赖性抑制剂。值得注意的是，H2AX 映射到人类癌症中经常改变的细胞遗传学区域，可能暗示人类具有类似的功能。
We employed gene targeting to study H2AX, a histone variant phosphorylated in chromatin surrounding DNA double-strand breaks. Mice deficient for both H2AX and p53 ((HP-/-)-P-Delta/Delta) rapidly developed immature T and B lymphomas and solid tumors. Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas. Most H2AX(Delta/Delta)p53(-/-) or H2AX(+/Delta) p53(-/-) B lineage lymphomas harbored chromosome 12 (IgH)/15 (c-myc) translocations with hallmarks of either aberrant V(D)J or class switch recombination. In contrast, H2AX(Delta/Delta)p53(-/-) thymic lymphomas had clonal translocations that did not involve antigen receptor loci and which likely occurred during cellular expansion. Thus, H2AX helps prevent aberrant repair of both programmed and general DNA breakage and, thereby, functions as a dosage-dependent suppressor of genomic instability and tumors in mice. Notably, H2AX maps to a cytogenetic region frequently altered in human cancers, possibily implicating similar functions in man.