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  1. Article ; Online: Exploring the Molecular Underpinnings of Cancer-Causing Oncohistone Mutants Using Yeast as a Model.

    Zhang, Xinran / Fawwal, Dorelle V / Spangle, Jennifer M / Corbett, Anita H / Jones, Celina Y

    Journal of fungi (Basel, Switzerland)

    2023  Volume 9, Issue 12

    Abstract: Understanding the molecular basis of cancer initiation and progression is critical in developing effective treatment strategies. Recently, mutations in genes encoding histone proteins that drive oncogenesis have been identified, converting these ... ...

    Abstract Understanding the molecular basis of cancer initiation and progression is critical in developing effective treatment strategies. Recently, mutations in genes encoding histone proteins that drive oncogenesis have been identified, converting these essential proteins into "oncohistones". Understanding how oncohistone mutants, which are commonly single missense mutations, subvert the normal function of histones to drive oncogenesis requires defining the functional consequences of such changes. Histones genes are present in multiple copies in the human genome with 15 genes encoding histone H3 isoforms, the histone for which the majority of oncohistone variants have been analyzed thus far. With so many wildtype histone proteins being expressed simultaneously within the oncohistone, it can be difficult to decipher the precise mechanistic consequences of the mutant protein. In contrast to humans, budding and fission yeast contain only two or three histone H3 genes, respectively. Furthermore, yeast histones share ~90% sequence identity with human H3 protein. Its genetic simplicity and evolutionary conservation make yeast an excellent model for characterizing oncohistones. The power of genetic approaches can also be exploited in yeast models to define cellular signaling pathways that could serve as actionable therapeutic targets. In this review, we focus on the value of yeast models to serve as a discovery tool that can provide mechanistic insights and inform subsequent translational studies in humans.
    Language English
    Publishing date 2023-12-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2784229-0
    ISSN 2309-608X ; 2309-608X
    ISSN (online) 2309-608X
    ISSN 2309-608X
    DOI 10.3390/jof9121187
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Hyperextended telomeres promote C-circle formation in telomerase positive human cells.

    Jones, Celina Y / Williams, Christopher L / Moreno, Sara P / Morris, Danna K / Mondello, Chiara / Karlseder, Jan / Bertuch, Alison A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type ... ...

    Abstract Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post
    Language English
    Publishing date 2023-01-27
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.26.525615
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.

    Jones, Celina Y / Williams, Christopher L / Moreno, Sara Priego / Morris, Danna K / Mondello, Chiara / Karlseder, Jan / Bertuch, Alison A

    The Journal of biological chemistry

    2023  Volume 299, Issue 5, Page(s) 104665

    Abstract: Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C- ... ...

    Abstract Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect circular DNA with extrachromosomal telomere repeats. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.
    MeSH term(s) Humans ; DNA Helicases/metabolism ; DNA, Circular ; Telomerase/metabolism ; Telomere/genetics ; Telomere/metabolism ; Telomere Homeostasis ; Cell Line ; HeLa Cells ; DNA Replication ; Hydroxyurea ; DNA Repair
    Chemical Substances DNA Helicases (EC 3.6.4.-) ; DNA, Circular ; FANCM protein, human (EC 3.6.1.-) ; Telomerase (EC 2.7.7.49) ; Hydroxyurea (X6Q56QN5QC)
    Language English
    Publishing date 2023-03-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104665
    Database MEDical Literature Analysis and Retrieval System OnLINE

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