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

• Published in: Nature structural & molecular biology Vol. 21; no. 2; pp. 167 - 174
• Main Authors: O'Sullivan, Roderick J, Arnoult, Nausica, Lackner, Daniel H, Oganesian, Liana, Haggblom, Candy, Corpet, Armelle, Almouzni, Genevieve, Karlseder, Jan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2014; Nature Publishing Group
• Subjects: 631/67; 631/80/83; Biochemistry; Biological Microscopy; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Line, Tumor; Cells; Chromosomes; Deoxyribonucleic acid; DNA; DNA Replication; Gene Expression Regulation; Humans; Kinetics; Leukemia; Life Sciences; Mammals; Membrane Biology; Molecular chaperones; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Molecular Chaperones - physiology; Pancreas; Physiological aspects; Protein Structure; Structure; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere Homeostasis - genetics; Telomeres; United States
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/nsmb.2754

Some cancer cells lacking telomerase activity extend their telomeres via an alternative, recombination-based mechanism, termed ALT. A new study shows that depletion of histone chaperone ASF1 can induce ALT in both primary and cancer cells, suggesting that the ALT pathway may be triggered by changes in chromatin state. 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.