The SNF2 family of ATPases acts in the context of chromatin to regulate transcription, replication, repair and recombination. Defects in SNF2 genes cause many human diseases. For example, mutations in SMARCAL1 (also named HARP) cause Schimke immuno-osseous dysplasia (SIOD); a multi-system disorder characterized by growth defects, immune deficiencies, renal failure and other complex phenotypes. Several groups including ours recently identified SMARCAL1 as a replication stress response protein. Importantly, SMARCAL1 localizes to stalled replication forks and this localization of SMARCAL1 activity prevents DNA damage accumulation during DNA replication. We determined that SIOD-related SMARCAL1 mutants could not prevent replication-associated DNA damage in cells in which endogenous SMARCAL1 was silenced, establishing the first link between SIOD and a defect in a specific biological activity. Here, we also report that cells from patients with SIOD exhibit elevated levels of DNA damage that can be rescued by re-introduction of wild-type SMARCAL1. Our data suggest that loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of SIOD.

中文翻译：

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SMARCAL1 和复制压力：对 SIOD 的解释？

ATPases 的 SNF2 家族在染色质的背景下起作用，以调节转录、复制、修复和重组。SNF2 基因的缺陷会导致许多人类疾病。例如，SMARCAL1（也称为 HARP）的突变会导致 Schimke 免疫骨发育不良（SIOD）；一种以生长缺陷、免疫缺陷、肾功能衰竭和其他复杂表型为特征的多系统疾病。包括我们在内的几个小组最近将 SMARCAL1 鉴定为一种复制应激反应蛋白。重要的是，SMARCAL1 定位于停滞的复制叉，并且 SMARCAL1 活性的这种定位可以防止 DNA 复制过程中 DNA 损伤的积累。我们确定 SIOD 相关的 SMARCAL1 突变体不能阻止内源性 SMARCAL1 沉默的细胞中与复制相关的 DNA 损伤，在 SIOD 和特定生物活性缺陷之间建立第一个联系。在这里，我们还报告了来自 SIOD 患者的细胞表现出升高的 DNA 损伤水平，可以通过重新引入野生型 SMARCAL1 来挽救。我们的数据表明，患者 SMARCAL1 功能的丧失可能导致 DNA 复制相关的基因组不稳定，从而导致 SIOD 的多效性表型。