Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of Alternative Lengthening of Telomeres.

Abstract

Alternative Lengthening of Telomeres (ALT) is a non-telomerase mechanism of telomere lengthening that occurs in about 10% of cancers overall and is particularly common in astrocytic brain tumors and specific types of sarcomas. Somatic cell hybridization analyses have previously shown that normal telomerase-negative fibroblasts and telomerase-positive immortalized cell lines contain repressors of ALT activity, indicating that activation of ALT results from loss of one or more unidentified repressors. More recently, ATRX or DAXX was shown to be mutated both in tumors with telomere lengths suggestive of ALT activity and in ALT cell lines. Here, an ALT cell line was separately fused to each of four telomerase-positive cell lines, and four or five independent hybrid lines from each fusion were examined for expression of ATRX and DAXX and for telomere lengthening mechanism. The hybrid lines expressed either telomerase or ALT, with the other mechanism being repressed. DAXX was expressed normally in all parental cell lines and in all of the hybrids. ATRX was expressed normally in each of the four telomerase-positive parental cell lines and in every telomerase-positive hybrid line, and was abnormal in the ALT parental cells and in all but one of the ALT hybrids. This correlation between ALT activity and loss of ATRX expression is consistent with ATRX being a repressor of ALT.

• Authors: Kylie Bower, Christine E Napier, Sara L Cole, Rebecca A Dagg, Loretta M S Lau, Emma L Duncan, Elsa L Moy, Roger R Reddel
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e50062 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23185534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Co-Repressor Proteins
• DAXX protein, human
• Molecular Chaperones
• Nuclear Proteins
• Repressor Proteins
• Telomerase
• DNA Helicases
• ATRX protein, human
• X-linked Nuclear Protein

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Cell Fusion
• Co-Repressor Proteins
• DNA Helicases (genetics, metabolism)
• Female
• Gene Expression Regulation
• Humans
• Hybrid Cells (metabolism, pathology)
• Male
• Molecular Chaperones
• Nuclear Proteins (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Telomerase (genetics, metabolism)
• Telomere
• Telomere Homeostasis (genetics)
• X-linked Nuclear Protein