The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT)

Nat Commun. 2019 May 28;10(1):2252. doi: 10.1038/s41467-019-10180-6.

Abstract

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Helicases / metabolism*
  • DNA Replication
  • DNA Topoisomerases, Type I / metabolism*
  • DNA-Binding Proteins / metabolism*
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Neoplasms / metabolism*
  • Nuclear Proteins / metabolism*
  • RecQ Helicases / metabolism*
  • Telomere / metabolism*
  • Telomere Homeostasis*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RMI1 protein, human
  • RMI2 protein, human
  • Bloom syndrome protein
  • FANCM protein, human
  • DNA Helicases
  • RecQ Helicases
  • DNA Topoisomerases, Type I