Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.

Abstract

The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.

• Authors: Roderick J O'Sullivan, Nausica Arnoult, Daniel H Lackner, Liana Oganesian, Candy Haggblom, Armelle Corpet, Genevieve Almouzni, Jan Karlseder
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 21 Issue 2 Pg. 167-74 (Feb 2014) ISSN: 1545-9985 [Electronic] United States
• PMID: 24413054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ASF1A protein, human
• ASF1B protein, human
• Cell Cycle Proteins
• Molecular Chaperones
• TERT protein, human
• Telomerase

Topics

• Cell Cycle Proteins (genetics, metabolism, physiology)
• Cell Line, Tumor
• DNA Replication
• Gene Expression Regulation
• Humans
• Kinetics
• Molecular Chaperones (genetics, metabolism, physiology)
• Telomerase (genetics, metabolism)
• Telomere Homeostasis (genetics)