Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress

Abstract

Summary: 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. : Schlafen 11 (SLFN11), a promising therapeutic biomarker, binds chromatin and sensitizes cancer cells to DNA-targeting agents by blocking DNA replication. Murai et al. show that, in response to replication stress, SLFN11 selectively increases chromatin accessibility at promoters and activates a subset of genes known as the immediate early genes (IEGs). Keywords: chromatin, replication stress, ATR, CHK1, cell cycle checkpoint, DNA damage, topoisomerase inhibitor, native immune response, JUN, FOS