SLFN11 Blocks Stressed Replication Forks Independently of ATR

Mol Cell. 2018 Feb 1;69(3):371-384.e6. doi: 10.1016/j.molcel.2018.01.012.


SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.

Keywords: ATAC-seq; ATR; CHK1; PARP inhibitors; SLFN11; camptothecin; cell cycle checkpoints; hydroxyurea; prexasertib (LY2606368); replication origin.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Camptothecin
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Chromatin / metabolism
  • DNA Damage
  • DNA Helicases / metabolism
  • DNA Replication / genetics
  • DNA Replication / physiology
  • DNA, Single-Stranded / genetics
  • DNA, Single-Stranded / metabolism
  • Humans
  • Minichromosome Maintenance Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pyrazines
  • Pyrazoles
  • Replication Protein A / metabolism


  • CDC45 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • DNA, Single-Stranded
  • Nuclear Proteins
  • Pyrazines
  • Pyrazoles
  • RPA1 protein, human
  • Replication Protein A
  • SLFN11 protein, human
  • prexasertib
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • DNA Helicases
  • Minichromosome Maintenance Proteins
  • Camptothecin