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Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells

Kathryn E Yost1,2, Sarah F Clatterbuck Soper1, Robert L Walker1

  • 1Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Scientific Reports
|March 16, 2019
PubMed

Insights

Alternative Lengthening of Telomeres (ALT) is a cancer mechanism linked to ATRX and DAXX genes. Restoring DAXX function in tumors halts ALT by enabling ATRX/DAXX complex localization to PML bodies.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Epigenetics

Background:

  • Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism in a subset of cancers.
  • ALT is frequently associated with mutations in ATRX and DAXX, key components of the H3.3 histone chaperone complex.
  • The precise role of ATRX and DAXX in ALT regulation is not fully understood.

Purpose of the Study:

  • To investigate the role of DAXX in the alternative lengthening of telomeres (ALT) mechanism.
  • To characterize DAXX function in an osteosarcoma cell line with a DAXX loss-of-function mutation.
  • To determine the impact of DAXX on ATRX/DAXX complex localization to PML bodies and ALT suppression.

Main Methods:

  • Characterization of the G292 osteosarcoma cell line with wild-type ATRX and DAXX loss-of-function.
  • Functional assays to assess the alternative lengthening of telomeres (ALT) phenotype.
  • Immunofluorescence to track ATRX/DAXX complex localization to PML bodies.
  • DAXX re-expression studies using an inducible system.

Main Results:

  • The G292 cell line, despite wild-type ATRX, exhibits an alternative lengthening of telomeres (ALT) phenotype due to DAXX loss-of-function.
  • The ATRX/DAXX complex fails to localize to nuclear PML bodies in DAXX-deficient G292 cells.
  • Reintroduction of wild-type DAXX suppresses the ALT phenotype and restores ATRX/DAXX localization to PML bodies.
  • Inducible DAXX expression rapidly disrupts ALT-associated PML bodies, and ALT is restored upon DAXX withdrawal.

Conclusions:

  • DAXX is essential for the alternative lengthening of telomeres (ALT) mechanism, independent of ATRX status.
  • DAXX's function in ALT relies on its localization to PML bodies, facilitating the ATRX/DAXX complex.
  • Targeting DAXX function or its localization may represent a therapeutic strategy for ALT-driven cancers.

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