Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Department of Biology/VGN Proteomics Facility, University of Vermont, Burlington, VT 05405, USA.
Cell Rep. 2018 Sep 18;24(12):3251-3261. doi: 10.1016/j.celrep.2018.08.065.
The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response.
DNA 解旋酶 FANCJ 突变与遗传性乳腺癌和卵巢癌以及范可尼贫血（FA）有关。然而，FANCJ 的缺失如何转化为疾病发病机制仍不清楚。我们通过分析有或没有 FANCJ 的细胞中与复制叉相关的蛋白质来解决这个问题。我们证明，FANCJ 敲除（FANCJ-KO）细胞中的复制体发生改变，与增强的复制应激一致，包括叉重排因子解旋酶样转录因子（HLTF）的异常积累。相应地，HLTF 有助于 FANCJ-KO 细胞中的叉降解。出乎意料的是，特征为 HLTF 缺陷细胞的无限制 DNA 合成是 FANCJ 依赖性的，与 S1 核酸酶敏感性和叉降解相关。这些结果表明，FANCJ 和 HLTF 促进复制叉完整性，部分通过相互拮抗来控制叉重排和延伸。表明一种蛋白质可以补偿另一种蛋白质的缺失，HLTF 和 FANCJ 的缺失都会导致更严重的复制应激反应。
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