BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres

EMBO J. 2017 Oct 2;36(19):2907-2919. doi: 10.15252/embj.201796889. Epub 2017 Sep 6.


Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events.

Keywords: ALT; BLM; SLX4; telomere recombination; telomere synthesis.

MeSH terms

  • Cells, Cultured
  • DNA Replication / genetics*
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type I / physiology
  • DNA-Directed DNA Polymerase / metabolism
  • DNA-Directed DNA Polymerase / physiology
  • Humans
  • Multienzyme Complexes / metabolism
  • Multienzyme Complexes / physiology
  • RecQ Helicases / metabolism
  • RecQ Helicases / physiology*
  • Recombinases / metabolism
  • Recombinases / physiology*
  • Recombination, Genetic / genetics*
  • Telomere / metabolism
  • Telomere Homeostasis / genetics*


  • Multienzyme Complexes
  • Recombinases
  • DNA synthesome
  • DNA-Directed DNA Polymerase
  • SLX4 protein, human
  • Bloom syndrome protein
  • RecQ Helicases
  • DNA Topoisomerases, Type I