Schlafen 11 (SLFN11) was recently discovered as a cellular restriction factor against replication stress. Here, we show that SLFN11 increases chromatin accessibility genome wide, prominently at active promoters in response to replication stress induced by the checkpoint kinase 1 (CHK1) inhibitor prexasertib or the topoisomerase I (TOP1) inhibitor camptothecin. Concomitantly, SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the immediate early genes (IEGs), including JUN, FOS, EGR1, NFKB2, and ATF3, together with the cell cycle arrest genes CDKN1A (p21WAF1) and GADD45. Both chromatin remodeling and IEG activation require the putative ATPase and helicase activity of SLFN11, whereas canonical extrinsic IEG activation is SLFN11 independent. SLFN11-dependent IEG activation by camptothecin is also observed across 55 non-isogenic NCI-60 cell lines. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the innate immune activation in response to replicative stress.

中文翻译：

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染色质重塑和SLFN11响应复制压力立即早期基因激活。

Schlafen 11（SLFN11）是最近发现的一种针对复制压力的细胞限制性因子。在这里，我们显示SLFN11增加了染色质可及性的全基因组范围，在响应于检查点激酶1（CHK1）抑制剂prexasertib或拓扑异构酶I（TOP1）喜树碱诱导的复制压力下，在活性启动子上显着。同时，SLFN11通过诱导包括JUN，FOS，EGR1，NFKB2和ATF3在内的立即早期基因（IEG）以及细胞周期阻滞基因CDKN1A（p21WAF1）和GADD45的转录来选择性激活细胞应激反应途径。染色质重塑和IEG激活均需要SLFN11的假定的ATPase和解旋酶活性，而经典的外在IEG激活则不依赖SLFN11。在55个非等基因NCI-60细胞系中也观察到喜树碱对SLFN11的IEG的激活作用。我们得出的结论是，SLFN11作为染色质结构的整体调节剂和内在的IEG激活剂，具有潜在的固有的免疫激活响应复制压力的能力。