Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R-loop removal. We show that UAP56 depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. We demonstrate an RNA–DNA helicase activity in UAP56 and show that its overexpression suppresses R loops and genome instability induced by depleting five different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA–DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful cotranscriptional RNA structures that otherwise would block transcription and replication.

中文翻译：

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UAP56 / DDX39B是一种主要的共转录RNA-DNA解旋酶，可消除全基因组中有害的R环。

非预定的R环代表DNA损伤和复制压力的主要来源。细胞具有防止R环积累的不同方法。一种机制依赖于保守的THO复合物与人类中依赖于RNA的ATP酶UAP56 / DDX39B和组蛋白修饰剂如SIN3脱乙酰基酶的共转录RNA加工因子相关。我们研究了UAP56 / DDX39B在R环去除中的功能。我们显示，UAP56耗竭会导致R环积累，R环介导的基因组不稳定和复制叉停滞。我们证明了UAP56中的RNA-DNA解旋酶活性，并表明它的过表达抑制了由五个不同无关因素引起的R环和基因组的不稳定性。UAP56 / DDX39B定位于活性染色质，并阻止了RNA-DNA杂种在整个基因组中的积累。