Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability
Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability
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DOI：
10.1038/sj.emboj.7601574
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发表时间：
2007-03-07
期刊：
影响因子：
11.4
通讯作者：
Surralles, Jordi
中科院分区：
文献类型：
--
作者：
Bogliolo, Massimo;Lyakhovich, Alex;Surralles, Jordi
范可尼贫血（FA）是一种以骨髓衰竭和癌症易感性为特征的染色体脆性综合征。已知中央FA蛋白FANCD 2在DNA损伤后在一个知之甚少的过程中重新定位到染色质。在这里，我们已经诱导了DNA损伤的亚核积累，以证明组蛋白H2 AX是FA/BRCA通路的一个新的组成部分，以应对停滞的复制叉。对来自H2 AX敲除小鼠或表达不可磷酸化H2 AX（H2 AX（S136 A/S139 A））的细胞的分析表明，磷酸化H2 AX（γ H2 AX）是在停滞的复制叉处将FANCD 2募集到染色质所必需的。FANCD 2与γ H2 AX的结合是BRCA 1依赖性的，并且H2 AX缺陷或耗尽的细胞显示FA样表型，包括过量的染色单体型染色体畸变和对MMC的超敏反应。H2 AX缺陷细胞的这种MMC超敏性不会通过耗尽FANCD 2而进一步增加，表明H2 AX和FANCD 2在响应DNA损伤诱导的复制阻断的相同途径中起作用。因此，组蛋白H2 AX在功能上与FA/BRCA通路连接，以解决停滞的复制叉并防止染色体不稳定性。
Fanconi anemia ( FA) is a chromosome fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AX(S136A/S139A)) indicate that phosphorylated H2AX (gamma H2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to gamma H2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatidtype chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability.