Bassing Craig H, Suh Heikyung, Ferguson David O, Chua Katrin F, Manis John, Eckersdorff Mark, Gleason Megan, Bronson Rodrick, Lee Charles, Alt Frederick W
Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard Medical School and The Center for Blood Research, Boston, MA 02115, USA.
Cell. 2003 Aug 8;114(3):359-70. doi: 10.1016/s0092-8674(03)00566-x.
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 (H(delta/delta)P(-/-)) 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, possibly implicating similar functions in man.
我们采用基因靶向技术研究H2AX，一种在DNA双链断裂周围染色质中被磷酸化的组蛋白变体。H2AX和p53均缺失的小鼠（H(δ/δ)P(-/-)）迅速发展出不成熟的T和B淋巴瘤以及实体瘤。此外，H2AX单倍体不足在正常细胞中导致基因组不稳定，并且在p53缺陷背景下，引发包括更成熟B淋巴瘤在内的各种肿瘤的早期发生。大多数H2AX(δ/δ)p53(-/-)或H2AX(+/δ)p53(-/-) B细胞系淋巴瘤携带12号染色体（IgH）/15号染色体（c-myc）易位，具有异常V(D)J或类别转换重组的特征。相比之下，H2AX(δ/δ)p53(-/-)胸腺淋巴瘤具有不涉及抗原受体基因座的克隆易位，这些易位可能发生在细胞扩增期间。因此，H2AX有助于防止程序性和一般性DNA断裂的异常修复，从而作为小鼠基因组不稳定和肿瘤的剂量依赖性抑制因子发挥作用。值得注意的是，H2AX定位于人类癌症中经常发生改变的细胞遗传学区域，可能在人类中具有类似功能。
