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Dive into the research topics where Hilda A. Pickett is active.

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Featured researches published by Hilda A. Pickett.


Nature Biotechnology | 2009

DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity

Jeremy D. Henson; Ying Cao; Lily I. Huschtscha; Andrew C. Chang; Amy Y.M. Au; Hilda A. Pickett; Roger R. Reddel

Alternative lengthening of telomeres (ALT) is likely to be an important target for anticancer treatment as ∼10% of cancers depend on this telomere maintenance mechanism for continued growth, and inhibition of ALT can cause cellular senescence. However, no ALT inhibitors have been developed for therapeutic use because of the lack of a suitable ALT activity assay and of known ALT-specific target molecules. Here we show that partially single-stranded telomeric (CCCTAA)n DNA circles (C-circles) are ALT specific. We provide an assay that is rapidly and linearly responsive to ALT activity and that is suitable for screening for ALT inhibitors. We detect C-circles in blood from ALT+ osteosarcoma patients, suggesting that the C-circle assay (CC assay) may have clinical utility for diagnosis and management of ALT+ tumors.


Nature Structural & Molecular Biology | 2009

Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions

Anthony J. Cesare; Zeenia Kaul; Scott B. Cohen; Christine E. Napier; Hilda A. Pickett; Axel A. Neumann; Roger R. Reddel

Telomere dysfunction is typically studied under conditions in which a component of the six-subunit shelterin complex that protects chromosome ends is disrupted. The nature of spontaneous telomere dysfunction is less well understood. Here we report that immortalized human cell lines lacking wild-type p53 function spontaneously show many telomeres with a DNA damage response (DDR), commonly affecting only one sister chromatid and not associated with increased chromosome end-joining. DDR+ telomeres represent an intermediate configuration between the fully capped and uncapped (fusogenic) states. In telomerase activity–positive (TA+) cells, DDR is associated with low TA and short telomeres. In cells using the alternative lengthening of telomeres mechanism (ALT+), DDR is partly independent of telomere length, mostly affects leading strand–replicated telomeres, and can be partly suppressed by TRF2 overexpression. In ALT+ (but not TA+) cells, DDR+ telomeres preferentially associate with large foci of extrachromosomal telomeric DNA and recombination proteins. DDR+ telomeres therefore arise through different mechanisms in TA+ and ALT+ cells and have different consequences.


The EMBO Journal | 2009

Control of telomere length by a trimming mechanism that involves generation of t-circles.

Hilda A. Pickett; Anthony J. Cesare; Rebecca L. Johnston; Axel A. Neumann; Roger R. Reddel

Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t‐circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction‐induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t‐loop resolution to form t‐circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself.


Cell Stem Cell | 2014

The Transcriptional and Functional Properties of Mouse Epiblast Stem Cells Resemble the Anterior Primitive Streak

Yoji Kojima; Keren Kaufman-Francis; Joshua B. Studdert; Kirsten A. Steiner; Melinda Power; David A.F. Loebel; Vanessa Jones; Angelyn Hor; Gustavo de Alencastro; Grant J. Logan; Erdahl Teber; Oliver H. Tam; Michael D. Stutz; Ian E. Alexander; Hilda A. Pickett; Patrick P.L. Tam

Mouse epiblast stem cells (EpiSCs) can be derived from a wide range of developmental stages. To characterize and compare EpiSCs with different origins, we derived a series of EpiSC lines from pregastrula stage to late-bud-stage mouse embryos. We found that the transcriptomes of these cells are hierarchically distinct from those of the embryonic stem cells, induced pluripotent stem cells (iPSCs), and epiblast/ectoderm. The EpiSCs display globally similar gene expression profiles irrespective of the original developmental stage of the source tissue. They are developmentally similar to the ectoderm of the late-gastrula-stage embryo and behave like anterior primitive streak cells when differentiated in vitro and in vivo. The EpiSC lines that we derived can also be categorized based on a correlation between gene expression signature and predisposition to differentiate into particular germ-layer derivatives. Our findings therefore highlight distinct identifying characteristics of EpiSCs and provide a foundation for further examination of EpiSC properties and potential.


Nucleic Acids Research | 2009

Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription

Laura J. Ng; Jennifer E. Cropley; Hilda A. Pickett; Roger R. Reddel; Catherine M. Suter

Tumours and immortalized cells avoid telomere attrition by using either the ribonucleoprotein enzyme telomerase or a recombination-based alternative lengthening of telomeres (ALT) mechanism. Available evidence from mice suggests that the epigenetic state of the telomere may influence the mechanism of telomere maintenance, but this has not been directly tested in human cancer. Here we investigated cytosine methylation directly adjacent to the telomere as a marker of the telomeres epigenetic state in a panel of human cell lines. We find that while ALT cells show highly heterogeneous patterns of subtelomeric methylation, subtelomeric regions in telomerase-positive cells invariably show denser methylation than normal cells, being almost completely methylated. When compared to matched normal and ALT cells, telomerase-positive cells also exhibit reduced levels of the telomeric repeat-containing-RNA (TERRA), whose transcription originates in the subtelomere. Our results are consistent with the notion that TERRA may inhibit telomerase: the heavy cytosine methylation we observe in telomerase-positive cells may reflect selection for TERRA silencing in order to facilitate telomerase activity at the telomere. These data suggest that the epigenetic differences between telomerase-positive and ALT cells may underlie the mechanism of telomere maintenance in human tumorigenesis and highlight the broad reaching consequences of epigenetic dysregulation in cancer.


Nature | 2017

Whole-genome landscapes of major melanoma subtypes

Nicholas K. Hayward; James S. Wilmott; Nicola Waddell; Peter A. Johansson; Matthew A. Field; Katia Nones; Ann Marie Patch; Hojabr Kakavand; Ludmil B. Alexandrov; Hazel Burke; Valerie Jakrot; Stephen Kazakoff; Oliver Holmes; Conrad Leonard; Radhakrishnan Sabarinathan; Loris Mularoni; Scott Wood; Qinying Xu; Nick Waddell; Varsha Tembe; Gulietta M. Pupo; Ricardo De Paoli-Iseppi; Ricardo E. Vilain; Ping Shang; Loretta Lau; Rebecca A. Dagg; Sarah-Jane Schramm; Antonia L. Pritchard; Ken Dutton-Regester; Felicity Newell

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.


Molecular and Cellular Biology | 2012

Telomerase Recruitment Requires both TCAB1 and Cajal Bodies Independently

J.L. Stern; K. G. Zyner; Hilda A. Pickett; Scott B. Cohen; Tracy M. Bryan

ABSTRACT The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. In human cells, recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR) and is also thought to rely on an N-terminal domain of the catalytic subunit, hTERT. We demonstrate that coilin, an essential structural component of Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence. In contrast, recruitment of telomerase was sensitive to levels of TCAB1, and this was not rescued by overexpression of telomerase. Thus, although Cajal bodies are important for recruitment, TCAB1 has an additional role in this process that is independent of these structures. TCAB1 itself localizes to telomeres in a telomerase-dependent but Cajal body-independent manner. We identify a point mutation in hTERT that largely abolishes recruitment yet does not affect association of telomerase with TCAB1, suggesting that this region mediates recruitment by an independent mechanism. Our results demonstrate that telomerase has multiple independent requirements for recruitment to telomeres and that the function of TCAB1 is to directly transport telomerase to telomeres.


Genes & Development | 2013

Alternative lengthening of telomeres in normal mammalian somatic cells

Axel A. Neumann; Catherine M. Watson; Jane R. Noble; Hilda A. Pickett; Patrick P.L. Tam; Roger R. Reddel

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.


Molecular Biology of the Cell | 2012

RTEL1 contributes to DNA replication and repair and telomere maintenance

Evert-Jan Uringa; Kathleen Lisaingo; Hilda A. Pickett; Julie Brind'Amour; Jan-Hendrik Rohde; Alex Zelensky; Jeroen Essers; Peter M. Lansdorp

Telomere maintenance and DNA repair are important processes that protect the genome. The essential helicase mRtel1 functions in homologous recombination repair and replication. In addition, telomeres in mRtel-deficient ES cells appear relatively stable in length, suggesting that mRtel1 is required to allow extension by telomerase.


Frontiers in Oncology | 2013

Alternative lengthening of telomeres: remodeling the telomere architecture

Dimitri Conomos; Hilda A. Pickett; Roger R. Reddel

To escape from the normal limits on proliferative potential, cancer cells must employ a means to counteract the gradual telomere attrition that accompanies semi-conservative DNA replication. While the majority of human cancers do this by up-regulating telomerase enzyme activity, most of the remainder use a homologous recombination-mediated mechanism of telomere elongation known as alternative lengthening of telomeres (ALT). Many molecular details of the ALT pathway are unknown, and even less is known regarding the mechanisms by which this pathway is activated. Here, we review current findings about telomere structure in ALT cells, including DNA sequence, shelterin content, and heterochromatic state. We speculate that remodeling of the telomere architecture may contribute to the emergence and maintenance of the ALT phenotype.

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Roger R. Reddel

Children's Medical Research Institute

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Axel A. Neumann

Children's Medical Research Institute

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Michael D. Stutz

Children's Medical Research Institute

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Christine E. Napier

Children's Medical Research Institute

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Rebecca A. Dagg

Children's Hospital at Westmead

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Dimitri Conomos

Children's Medical Research Institute

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Jeremy D. Henson

Children's Medical Research Institute

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Jonathan Beesley

QIMR Berghofer Medical Research Institute

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