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  1. Article ; Online: UV light-induced dual promoter mutations dismantle the telomeric guardrails in melanoma.

    Sanford, Samantha L / Opresko, Patricia L

    DNA repair

    2022  Volume 122, Page(s) 103446

    Abstract: Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this ... ...

    Abstract Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this most deadly form of skin cancer. UV-induced mutations in the telomerase TERT gene promoter occur in the majority of melanomas but fail to prevent telomere shortening despite telomerase upregulation. This suggests additional "hits" are required to enable telomere maintenance. A new study in Science identified somatic variants in the promoter of the gene that encodes telomere shelterin protein TPP1 in human melanomas. These variants show mutational signatures of UV-induced DNA damage and upregulate TPP1 expression, which synergizes with telomerase to lengthen telomeres. This study provides evidence that TPP1 promoter variants are a critical second hit to prevent telomere shortening and promote immortalization of melanoma cells.
    MeSH term(s) Humans ; Telomerase/genetics ; Telomerase/metabolism ; Ultraviolet Rays/adverse effects ; Telomere/metabolism ; Telomere-Binding Proteins/genetics ; Telomere-Binding Proteins/metabolism ; Melanoma/genetics ; Mutation
    Chemical Substances Telomerase (EC 2.7.7.49) ; Telomere-Binding Proteins
    Language English
    Publishing date 2022-12-30
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2022.103446
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: How DNA damage and non-canonical nucleotides alter the telomerase catalytic cycle.

    Sanford, Samantha L / Welfer, Griffin A / Freudenthal, Bret D / Opresko, Patricia L

    DNA repair

    2021  Volume 107, Page(s) 103198

    Abstract: Telomeres at the ends of linear chromosomes are essential for genome maintenance and sustained cellular proliferation, but shorten with each cell division. Telomerase, a specialized reverse transcriptase with its own integral RNA template, compensates ... ...

    Abstract Telomeres at the ends of linear chromosomes are essential for genome maintenance and sustained cellular proliferation, but shorten with each cell division. Telomerase, a specialized reverse transcriptase with its own integral RNA template, compensates for this by lengthening the telomeric 3' single strand overhang. Mammalian telomerase has the unique ability to processively synthesize multiple GGTTAG repeats, by translocating along its product and reiteratively copying the RNA template, termed repeat addition processivity (RAP). This unusual form of processivity is distinct from the nucleotide addition processivity (NAP) shared by all other DNA polymerases. In this review, we focus on the minimally active human telomerase catalytic core consisting of the telomerase reverse transcriptase (TERT) and the integral RNA (TR), which catalyzes DNA synthesis. We review the mechanisms by which oxidatively damaged nucleotides, and anti-viral and anti-cancer nucleotide drugs affect the telomerase catalytic cycle. Finally, we offer perspective on how we can leverage telomerase's unique properties, and advancements in understanding of telomerase catalytic mechanism, to selectively manipulate telomerase activity with therapeutics, particularly in cancer treatment.
    MeSH term(s) Telomerase
    Chemical Substances Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2021-07-31
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2021.103198
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs.

    Sanford, Samantha L / Welfer, Griffin A / Freudenthal, Bret D / Opresko, Patricia L

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 5288

    Abstract: Telomerase is a specialized reverse transcriptase that adds GGTTAG repeats to chromosome ends and is upregulated in most human cancers to enable limitless proliferation. Here, we uncover two distinct mechanisms by which naturally occurring oxidized dNTPs ...

    Abstract Telomerase is a specialized reverse transcriptase that adds GGTTAG repeats to chromosome ends and is upregulated in most human cancers to enable limitless proliferation. Here, we uncover two distinct mechanisms by which naturally occurring oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation. We conduct a series of direct telomerase extension assays in the presence of modified dNTPs on various telomeric substrates. We provide direct evidence that telomerase can add the nucleotide reverse transcriptase inhibitors ddITP and AZT-TP to the telomeric end, causing chain termination. In contrast, telomerase continues elongation after inserting oxidized 2-OH-dATP or therapeutic 6-thio-dGTP, but insertion disrupts translocation and inhibits further repeat addition. Kinetics reveal that telomerase poorly selects against 6-thio-dGTP, inserting with similar catalytic efficiency as dGTP. Furthermore, telomerase processivity factor POT1-TPP1 fails to restore processive elongation in the presence of inhibitory dNTPs. These findings reveal mechanisms for targeting telomerase with modified dNTPs in cancer therapy.
    MeSH term(s) Deoxyadenine Nucleotides/chemistry ; Deoxyadenine Nucleotides/metabolism ; Deoxyguanine Nucleotides/chemistry ; Deoxyguanine Nucleotides/metabolism ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Humans ; Kinetics ; Models, Molecular ; Oxidation-Reduction ; Shelterin Complex ; Telomerase/antagonists & inhibitors ; Telomerase/chemistry ; Telomerase/genetics ; Telomerase/metabolism ; Telomere/metabolism ; Telomere-Binding Proteins
    Chemical Substances ACD protein, human ; Deoxyadenine Nucleotides ; Deoxyguanine Nucleotides ; Enzyme Inhibitors ; Shelterin Complex ; Telomere-Binding Proteins ; deoxyguanosine triphosphate (8C2O37Y44Q) ; Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2020-10-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-19115-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: BG4 antibody can recognize telomeric G-quadruplexes harboring destabilizing base modifications and lesions.

    Johnson, Samuel A / Paul, Tapas / Sanford, Samantha L / Schnable, Brittani L / Detwiler, Ariana C / Thosar, Sanjana A / Van Houten, Bennett / Myong, Sua / Opresko, Patricia L

    Nucleic acids research

    2023  Volume 52, Issue 4, Page(s) 1763–1778

    Abstract: BG4 is a single-chain variable fragment antibody shown to bind various G-quadruplex (GQ) topologies with high affinity and specificity, and to detect GQ in cells, including GQ structures formed within telomeric TTAGGG repeats. Here, we used ELISA and ... ...

    Abstract BG4 is a single-chain variable fragment antibody shown to bind various G-quadruplex (GQ) topologies with high affinity and specificity, and to detect GQ in cells, including GQ structures formed within telomeric TTAGGG repeats. Here, we used ELISA and single-molecule pull-down (SiMPull) detection to test how various lengths and GQ destabilizing base modifications in telomeric DNA constructs alter BG4 binding. We observed high-affinity BG4 binding to telomeric GQ independent of telomere length, although three telomeric repeat constructs that cannot form stable intramolecular GQ showed reduced affinity. A single guanine substitution with 8-aza-7-deaza-G, T, A, or C reduced affinity to varying degrees depending on the location and base type, whereas two G substitutions in the telomeric construct dramatically reduced or abolished binding. Substitution with damaged bases 8-oxoguanine and O6-methylguanine failed to prevent BG4 binding although affinity was reduced depending on lesion location. SiMPull combined with FRET revealed that BG4 binding promotes folding of telomeric GQ harboring a G to T substitution or 8-oxoguanine. Atomic force microscopy revealed that BG4 binds telomeric GQ with a 1:1 stoichiometry. Collectively, our data suggest that BG4 can recognize partially folded telomeric GQ structures and promote telomeric GQ stability.
    MeSH term(s) G-Quadruplexes ; DNA/genetics ; DNA/chemistry ; Telomere/genetics ; Antibodies/genetics
    Chemical Substances DNA (9007-49-2) ; Antibodies
    Language English
    Publishing date 2023-12-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad1209
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  5. Article ; Online: Mechanisms of nucleotide selection by telomerase.

    Schaich, Matthew A / Sanford, Samantha L / Welfer, Griffin A / Johnson, Samuel A / Khoang, Thu H / Opresko, Patricia L / Freudenthal, Bret D

    eLife

    2020  Volume 9

    Abstract: Telomerase extends telomere sequences at chromosomal ends to protect genomic DNA. During this process it must select the correct nucleotide from a pool of nucleotides with various sugars and base pairing properties, which is critically important for the ... ...

    Abstract Telomerase extends telomere sequences at chromosomal ends to protect genomic DNA. During this process it must select the correct nucleotide from a pool of nucleotides with various sugars and base pairing properties, which is critically important for the proper capping of telomeric sequences by shelterin. Unfortunately, how telomerase selects correct nucleotides is unknown. Here, we determined structures of
    MeSH term(s) Animals ; Base Pairing/genetics ; Catalytic Domain ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; Humans ; Insect Proteins/chemistry ; Insect Proteins/genetics ; Insect Proteins/metabolism ; Models, Molecular ; Nucleotides/chemistry ; Nucleotides/genetics ; Nucleotides/metabolism ; Protein Binding ; Telomerase/chemistry ; Telomerase/genetics ; Telomerase/metabolism ; Tribolium/enzymology ; Tribolium/genetics ; Tyrosine/chemistry ; Tyrosine/genetics ; Tyrosine/metabolism
    Chemical Substances Insect Proteins ; Nucleotides ; Tyrosine (42HK56048U) ; DNA (9007-49-2) ; Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2020-06-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.55438
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