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

Cell Rep. 2020 Mar 24;30(12):4137-4151.e6. doi: 10.1016/j.celrep.2020.02.117.

Abstract

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.

Keywords: ATR; CHK1; DNA damage; FOS; JUN; cell cycle checkpoint; chromatin; native immune response; replication stress; topoisomerase inhibitor.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cell Line
  • Chromatin Assembly and Disassembly / genetics*
  • DNA Helicases / metabolism
  • DNA Replication / genetics*
  • Genes, Immediate-Early*
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress, Physiological / genetics*
  • Transcription, Genetic
  • Transcriptional Activation / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Nuclear Proteins
  • RNA, Messenger
  • SLFN11 protein, human
  • Tumor Suppressor Protein p53
  • Adenosine Triphosphatases
  • DNA Helicases