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  1. Article ; Online: APOBEC-Induced Mutagenesis in Cancer.

    Mertz, Tony M / Collins, Christopher D / Dennis, Madeline / Coxon, Margo / Roberts, Steven A

    Annual review of genetics

    2022  Volume 56, Page(s) 229–252

    Abstract: The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis and hinder the development of long-lasting therapeutics. Recent ... ...

    Abstract The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis and hinder the development of long-lasting therapeutics. Recent sequencing of human cancer genomes has identified patterns of mutations, termed mutation signatures, many of which correspond to specific environmentally induced and endogenous mutation processes. Some of the most frequently observed mutation signatures are caused by dysregulated activity of APOBECs, which deaminate cytidines in single-stranded DNA at specific sequence motifs causing C-to-T and C-to-G substitutions. In humans, APOBEC-generated genetic heterogeneity in tumor cells contributes to carcinogenesis, metastasis, and resistance to therapeutics. Here, we review the current understanding of APOBECs' role in cancer mutagenesis and impact on disease and the biological processes that influence APOBEC mutagenic capacity.
    MeSH term(s) Humans ; Mutagenesis/genetics ; Neoplasms/genetics ; Cell Nucleus ; Mutation ; Carcinogenesis/genetics
    Language English
    Publishing date 2022-08-26
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 207928-8
    ISSN 1545-2948 ; 0066-4170 ; 0066-4197
    ISSN (online) 1545-2948
    ISSN 0066-4170 ; 0066-4197
    DOI 10.1146/annurev-genet-072920-035840
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1109: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Single-stranded DNA binding proteins influence APOBEC3A substrate preference.

    Brown, Amber L / Collins, Christopher D / Thompson, Secily / Coxon, Margo / Mertz, Tony M / Roberts, Steven A

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 21008

    Abstract: The cytidine deaminase, APOBEC3A (A3A), is a prominent source of mutations in multiple cancer types. These APOBEC-signature mutations are non-uniformly distributed across cancer genomes, associating with single-stranded (ss) DNA formed during DNA ... ...

    Abstract The cytidine deaminase, APOBEC3A (A3A), is a prominent source of mutations in multiple cancer types. These APOBEC-signature mutations are non-uniformly distributed across cancer genomes, associating with single-stranded (ss) DNA formed during DNA replication and hairpin-forming sequences. The biochemical and cellular factors that influence these specificities are unclear. We measured A3A's cytidine deaminase activity in vitro on substrates that model potential sources of ssDNA in the cell and found that A3A is more active on hairpins containing 4 nt ssDNA loops compared to hairpins with larger loops, bubble structures, replication fork mimics, ssDNA gaps, or linear DNA. Despite pre-bent ssDNAs being expected to fit better in the A3A active site, we determined A3A favors a 4 nt hairpin substrate only 2- to fivefold over linear ssDNA substrates. Addition of whole cell lysates or purified RPA to cytidine deaminase assays more severely reduced A3A activity on linear ssDNA (45 nt) compared to hairpin substrates. These results indicate that the large enrichment of A3A-driven mutations in hairpin-forming sequences in tumor genomes is likely driven in part by other proteins that preferentially bind longer ssDNA regions, which limit A3A's access. Furthermore, A3A activity is reduced at ssDNA associated with a stalled T7 RNA polymerase, suggesting that potential protein occlusion by RNA polymerase also limits A3A activity. These results help explain the small transcriptional strand bias for APOBEC mutation signatures in cancer genomes and the general targeting of hairpin-forming sequences in the lagging strand template during DNA replication.
    MeSH term(s) Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; DNA Replication ; DNA, Single-Stranded/chemistry ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Gene Expression ; Humans ; Nucleic Acid Conformation ; Protein Binding ; Proteins/genetics ; Proteins/metabolism ; Substrate Specificity ; Transcription, Genetic
    Chemical Substances DNA, Single-Stranded ; DNA-Binding Proteins ; Proteins ; APOBEC3A protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5)
    Language English
    Publishing date 2021-10-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-00435-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An impaired ubiquitin-proteasome system increases APOBEC3A abundance.

    Coxon, Margo / Dennis, Madeline A / Dananberg, Alexandra / Collins, Christopher D / Wilson, Hannah E / Meekma, Jordyn / Savenkova, Marina I / Ng, Daniel / Osbron, Chelsea A / Mertz, Tony M / Goodman, Alan G / Duttke, Sascha H / Maciejowski, John / Roberts, Steven A

    NAR cancer

    2023  Volume 5, Issue 4, Page(s) zcad058

    Abstract: Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms ... ...

    Abstract Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.
    Language English
    Publishing date 2023-12-19
    Publishing country England
    Document type Journal Article
    ISSN 2632-8674
    ISSN (online) 2632-8674
    DOI 10.1093/narcan/zcad058
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.

    Crook, Zachary R / Girard, Emily / Sevilla, Gregory P / Merrill, Morgan / Friend, Della / Rupert, Peter B / Pakiam, Fiona / Nguyen, Elizabeth / Yin, Chunfeng / Ruff, Raymond O / Hopping, Gene / Strand, Andrew D / Finton, Kathryn A K / Coxon, Margo / Mhyre, Andrew J / Strong, Roland K / Olson, James M

    Journal of molecular biology

    2020  Volume 432, Issue 14, Page(s) 3989–4009

    Abstract: The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes ... ...

    Abstract The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drugs or drug-delivery vehicles. Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (K
    MeSH term(s) Animals ; Antigens, CD/chemistry ; Antigens, CD/drug effects ; Antigens, CD/genetics ; Antigens, CD/pharmacology ; Blood-Brain Barrier/drug effects ; Central Nervous System/drug effects ; Central Nervous System Diseases/drug therapy ; Cystine/chemistry ; Cystine/genetics ; Drug Delivery Systems ; Humans ; Inflammation/drug therapy ; Inflammation/pathology ; Mice ; Neuropeptides/chemistry ; Neuropeptides/pharmacology ; Neurotensin/chemistry ; Neurotensin/pharmacology ; Peptides/chemistry ; Peptides/pharmacology ; Protein Binding/drug effects ; Receptors, Transferrin/chemistry ; Receptors, Transferrin/drug effects ; Receptors, Transferrin/genetics
    Chemical Substances Antigens, CD ; CD71 antigen ; Neuropeptides ; Peptides ; Receptors, Transferrin ; Neurotensin (39379-15-2) ; Cystine (48TCX9A1VT)
    Language English
    Publishing date 2020-04-15
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2020.04.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

    Bandopadhayay, Pratiti / Piccioni, Federica / O'Rourke, Ryan / Ho, Patricia / Gonzalez, Elizabeth M / Buchan, Graham / Qian, Kenin / Gionet, Gabrielle / Girard, Emily / Coxon, Margo / Rees, Matthew G / Brenan, Lisa / Dubois, Frank / Shapira, Ofer / Greenwald, Noah F / Pages, Melanie / Balboni Iniguez, Amanda / Paolella, Brenton R / Meng, Alice /
    Sinai, Claire / Roti, Giovanni / Dharia, Neekesh V / Creech, Amanda / Tanenbaum, Benjamin / Khadka, Prasidda / Tracy, Adam / Tiv, Hong L / Hong, Andrew L / Coy, Shannon / Rashid, Rumana / Lin, Jia-Ren / Cowley, Glenn S / Lam, Fred C / Goodale, Amy / Lee, Yenarae / Schoolcraft, Kathleen / Vazquez, Francisca / Hahn, William C / Tsherniak, Aviad / Bradner, James E / Yaffe, Michael B / Milde, Till / Pfister, Stefan M / Qi, Jun / Schenone, Monica / Carr, Steven A / Ligon, Keith L / Kieran, Mark W / Santagata, Sandro / Olson, James M / Gokhale, Prafulla C / Jaffe, Jacob D / Root, David E / Stegmaier, Kimberly / Johannessen, Cory M / Beroukhim, Rameen

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 2400

    Abstract: BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, ... ...

    Abstract BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
    MeSH term(s) Animals ; Azepines/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/drug effects ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; CRISPR-Cas Systems ; Cell Cycle/drug effects ; Cell Cycle Proteins/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Lineage ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/genetics ; Cyclin D2/drug effects ; Cyclin D2/metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Drug Resistance, Neoplasm ; Gene Expression Profiling ; Humans ; Medulloblastoma/drug therapy ; Medulloblastoma/genetics ; Mice ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Neurogenesis/drug effects ; Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; S Phase/drug effects ; Triazoles/pharmacology
    Chemical Substances (+)-JQ1 compound ; Azepines ; Basic Helix-Loop-Helix Transcription Factors ; Cell Cycle Proteins ; Cyclin D2 ; MYC protein, human ; Proteins ; Proto-Oncogene Proteins c-myc ; Triazoles ; bromodomain and extra-terminal domain protein, human ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
    Language English
    Publishing date 2019-06-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-10307-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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