Axel A. Neumann

Orthopädische Praxis

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Roger R. Reddel

University of Sydney

Hilda A. Pickett

Children's Medical Research Institute

Lily I. Huschtscha

Children's Medical Research Institute

Andy Chang

Children's Medical Research Institute

Tracy M. Bryan

Children's Medical Research Institute

Christian D. Toouli

Children's Medical Research Institute

Amanda Nouwens

University of Queensland

Jane R. Noble

Children's Medical Research Institute

Jeremy D. Henson

UNSW Sydney

Ying Cao

Southwest Hospital

Cooperative Institutions

Children's Medical Research Institute

University of Sydney

University of Wisconsin–Madison

University of Wisconsin Carbone Cancer Center

UW Health University Hospital

UNSW Sydney

Jena University Hospital

Children's Hospital at Westmead

Australian National University

Howard Hughes Medical Institute

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Endoskopische Dekompression des Karpaltunnels in der Agee-Technik modifiziert nach Neumann

Operative Orthopädie und Traumatologie (2023)

Axel A. Neumann T. Kponton

Retinaculum

10.1007/s00064-023-00804-y

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Citations (1)

Telomere elongation involves intra-molecular DNA replication in cells utilizing alternative lengthening of telomeres

Human Molecular Genetics (2008)

Anna Lisa Muntoni Axel A. Neumann Melissa J. Hills Roger R. Reddel

Alternative lengthening of telomeres (ALT) is a telomere length maintenance mechanism based on recombination, where telomeres use other telomeric DNA as a template for DNA synthesis. About 10% of all human tumors depend on ALT for their continued growth, and understanding its molecular details is critically important for the development of cancer treatments that target this mechanism. We have previously shown that telomeres of ALT-positive human cells can become lengthened via inter-telomeric copying, i.e. by copying the telomere of another chromosome. The possibility that such telomeres could elongate by using other sources of telomeric DNA as copy templates has not been investigated previously. In this study, we have determined whether a telomere can become lengthened by copying its own sequences, without the need for using another telomere as a copy template. To test this, we transduced an ALT cell line with a telomere-targeting construct and obtained clones with a single tagged telomere. We showed that the telomere tag can be amplified without the involvement of other telomeres, indicating that telomere elongation can also occur by intra-telomeric DNA copying. This is the first direct evidence that the ALT mechanism involves more than one method of telomere elongation.

Telomere-binding protein

Copying

10.1093/hmg/ddn436

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Citations (66)

Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body.

PubMed (1999)

Thomas R. Yeager Axel A. Neumann Anna Englezou Lily I. Huschtscha Jane R. Noble

Telomerase-negative immortalized human cells maintain their telomeres by a mechanism known as alternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat binding factors 1 and 2. Immunostaining showed that APBs also contain replication factor A, RAD51, and RAD52, proteins involved in DNA synthesis and recombination. During immortalization, APBs appeared at exactly the same time as activation of ALT. APBs were found in ALT tumors and cell lines but not in mortal cell strains or in telomerase-positive cell lines or tumors.

Promyelocytic leukemia protein

Immunostaining

Immortalised cell line

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Non‐telomerase telomere maintenance in human cells (97.2)

The FASEB Journal (2014)

Roger R. Reddel Dimitri Conomos Jeremy D. Henson Christine E. Napier Axel A. Neumann

Although it has recently been demonstrated that telomeres can be lengthened by a non‐telomerase mechanism (i.e., Alternative Lengthening of Telomeres; ALT) in normal mouse tissues, we have learnt most about ALT in mammalian cells from the study of in vitro ‐immortalized and tumor‐derived human cell lines. Apart from its intrinsic biological interest, it is important to understand ALT because ~10% of human cancers utilize it to avoid senescence, and some of the tumor types where ALT is common, such as soft tissue sarcomas and astrocytic brain tumors, are currently difficult to treat. Loss of normal ATRX or DAXX function contributes to, but is insufficient for the upregulation of ALT in many cancers and cell lines. An increased non‐canonical telomeric repeat sequence content may also foster increased levels of ALT activity by decreasing shelterin binding sites. ALT involves synthesis of new telomeric DNA via recombination‐mediated copying of existing telomeric sequences. The template may be the DNA of another telomere or a more proximal region of the telomere that is being lengthened. There is a tight correlation between the level of C‐circles, i.e., extrachromosomal circles of partially double‐stranded telomeric DNA with an intact C‐rich strand and an incomplete G‐rich strand, and ALT activity. We are therefore using a C‐circle assay to identify genes/ proteins involved in the ALT mechanism.

Shelterin

Extrachromosomal DNA

Senescence

Telomere-binding protein

Death-associated protein 6

ATRX

10.1096/fasebj.28.1_supplement.97.2

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Citations (0)

Coexistence of Alternative Lengthening of Telomeres and Telomerase in hTERT-Transfected GM847 Cells

Molecular and Cellular Biology (2001)

Kilian Perrem Lorel M. Colgin Axel A. Neumann Thomas R. Yeager Roger R. Reddel

It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce telomerase that is active at the telomere. However, rapid fluctuation in telomere length still occurred in the GM847/hTERT cells after more than 100 population doublings. Very long telomeres and ALT-associated promyelocytic leukemia (PML) bodies continued to be generated, indicating that telomerase activity induced by exogenous hTERT did not abolish the ALT mechanism. In contrast, when the GM847 cell line was fused with two different telomerase-positive tumor cell lines, the ALT phenotype was repressed in each case. These hybrid cells were telomerase positive, and the telomeres decreased in length, very rapidly at first and then at the rate seen in telomerase-negative normal cells. Additionally, ALT-associated PML bodies disappeared. After the telomeres had shortened sufficiently, they were maintained at a stable length by telomerase. Together these data indicate that the telomerase-positive cells contain a factor that represses the ALT mechanism but that this factor is unlikely to be telomerase. Further, the transfection data indicate that ALT and telomerase can coexist in the same cells.

Telomerase RNA component

10.1128/mcb.21.12.3862-3875.2001

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Citations (239)

Supplementary Figure 1 from Amplification of Telomerase Reverse Transcriptase Gene in Human Mammary Epithelial Cells with Limiting Telomerase RNA Expression Levels

Ying Cao Lily I. Huschtscha Amanda Nouwens Hilda A. Pickett Axel A. Neumann

Supplementary Figure 1 from Amplification of Telomerase Reverse Transcriptase Gene in Human Mammary Epithelial Cells with Limiting Telomerase RNA Expression Levels

Limiting

Telomerase RNA component

10.1158/0008-5472.22375656.v1

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BLM and SLX4 play opposing roles in recombination‐dependent replication at human telomeres

The EMBO Journal (2017)

Alexander P. Sobinoff Joshua A. M. Allen Axel A. Neumann Sile F. Yang Monica Eve Walsh

Telomere-binding protein

10.15252/embj.201796889

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Citations (138)

Pictures in Molecular Medicine: Telomeres copying telomeres in human cells

Trends in Molecular Medicine (2001)

Axel A. Neumann Clare L. Fasching

Senescence

10.1016/s1471-4914(01)01964-5

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Citations (1)

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

Cancer Research (2007)

Clare L. Fasching Axel A. Neumann Alessandra Muntoni Thomas R. Yeager Roger R. Reddel

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. [Cancer Res 2007;67(15):7072–7]

Extrachromosomal DNA

10.1158/0008-5472.can-07-1556

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Citations (86)

Alternative lengthening of telomeres in normal mammalian somatic cells

Genes & Development (2013)

Axel A. Neumann Catherine M. Watson Jane R. Noble Hilda A. Pickett Patrick Tam

Some cancers use alternative lengthening of telomeres (ALT), a mechanism whereby new telomeric DNA is synthesized from a DNA template. To determine whether normal mammalian tissues have ALT activity, we generated a mouse strain containing a DNA tag in a single telomere. We found that the tagged telomere was copied by other telomeres in somatic tissues but not the germline. The tagged telomere was also copied by other telomeres when introgressed into CAST/EiJ mice, which have telomeres more similar in length to those of humans. We conclude that ALT activity occurs in normal mouse somatic tissues.

Telomere-binding protein

10.1101/gad.205062.112

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Citations (128)