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.
Junko Murai  1 ,  Sai-Wen Tang  2 ,  Elisabetta Leo  2 ,  Simone A Baechler  2 ,  Christophe E Redon  2 ,  Hongliang Zhang  2 ,  Muthana Al Abo  2 ,  Vinodh N Rajapakse  2 ,  Eijiro Nakamura  3 ,  Lisa M Miller Jenkins  4 ,  Mirit I Aladjem  2 ,  Yves Pommier  5
Affiliations
  • 1. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 2. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 3. DSK project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8397, Japan.
  • 4. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 5. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 29395061 DOI: 10.1016/j.molcel.2018.01.012
Abstract

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.