Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres

Genes Dev. 2020 May 1;34(9-10):650-662. doi: 10.1101/gad.333963.119. Epub 2020 Mar 26.


Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We found that PML is required for the ALT mechanism, and that this necessity stems from APBs' role in localizing the BLM-TOP3A-RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.

Keywords: ALT; BLM; PML; telomere; telomere length.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • DNA Topoisomerases, Type I / metabolism*
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Protein Transport
  • RecQ Helicases / metabolism*
  • Telomere / genetics*
  • Telomere / metabolism*
  • Telomere Homeostasis / physiology*


  • DNA-Binding Proteins
  • RMI1 protein, human
  • Bloom syndrome protein
  • RecQ Helicases
  • TOP3A protein, human
  • DNA Topoisomerases, Type I