DNA Damage Induces Alternative Lengthening of Telomeres (ALT)-Associated Promyelocytic Leukemia Bodies that Preferentially Associate with Linear Telomeric DNA

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Fashcing, Clare, Neumann, Axel, Muntoni, Alessandra, Yeager, Thomas and Reddel, Roger (2007) DNA Damage Induces Alternative Lengthening of Telomeres (ALT)-Associated Promyelocytic Leukemia Bodies that Preferentially Associate with Linear Telomeric DNA. Cancer Research, 67 (15). pp. 7072-7077. ISSN 0008-5472

Abstract

The linear chromosomes of vertebrates terminate in telomeres that consist of a tandemly repeated hexameric sequence, 5′TTAGGG3′. Telomeres form a protective loop structure (t-loop), which is thought to prevent them from being recognized as a double-strand break. Approximately 10% of human tumors prevent shortening of their telomeres by using a recombination-mediated alternative lengthening of telomeres (ALT) mechanism. ALT-positive human cells contain extrachromosomal telomere repeat (ECTR) DNA that may either be circular or linear. It has been proposed that ECTR may be generated by recombination events involving the t-loop. A proportion of the cells within ALT-positive cell populations contain promyelocytic leukemia (PML) nuclear bodies that contain telomeric DNA and telomere-binding proteins that are called ALT-associated PML bodies (APB). Although the presence of APBs is very useful for determining whether tumors and cell lines use the ALT mechanism, the function of APBs is unknown. It has previously been shown that telomeric DNA is particularly susceptible to damage by hydrogen peroxide and N-methyl-N′-nitro-N-nitrosoguanidine. We report here that these DNA-damaging agents induce both linear and circular ECTR DNA in ALT cells and increase the proportion of cells that contain APBs. We partially purified APBs and showed that the telomeric repeat DNA they contain is predominantly linear. We propose that a function of APBs is to sequester linear telomeric DNA.

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Additional Information

Online ISSN: 1538-7445

Item type Article
URI https://vuir.vu.edu.au/id/eprint/8495
DOI https://doi.org/10.1158/0008-5472.CAN-07-1556
Official URL http://cancerres.aacrjournals.org/content/67/15/70...
Subjects Current > FOR Classification > 1101 Medical Biochemistry and Metabolomics
Current > FOR Classification > 1112 Oncology and Carcinogenesis
Historical > Faculty/School/Research Centre/Department > School of Engineering and Science
Keywords ResPubID19459. alternative lengthening of telomeres, ALT-associated, leukemia, PML bodies, DNA damage, extrachromosomal telomeric repeat DNA, chromosome
Citations in Scopus 65 - View on Scopus
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