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  • 1
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    Online Resource
    A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant
    Springer Science and Business Media LLC ; 2023
    In:  Oncogene Vol. 42, No. 36 ( 2023-09-01), p. 2701-2709
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 42, No. 36 ( 2023-09-01), p. 2701-2709
    Abstract: Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-023-02782-8
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
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    Quantification of the Spatial Organization of the Nuclear Lamina as a Tool for Cell Classification
    Hindawi Limited ; 2013
    In:  ISRN Molecular Biology Vol. 2013 ( 2013-11-07), p. 1-6
    Details
    In: ISRN Molecular Biology, Hindawi Limited, Vol. 2013 ( 2013-11-07), p. 1-6
    Abstract: The nuclear lamina is the structural scaffold of the nuclear envelope that plays multiple regulatory roles in chromatin organization and gene expression as well as a structural role in nuclear stability. The lamina proteins, also referred to as lamins, determine nuclear lamina organization and define the nuclear shape and the structural integrity of the cell nucleus. In addition, lamins are connected with both nuclear and cytoplasmic structures forming a dynamic cellular structure whose shape changes upon external and internal signals. When bound to the nuclear lamina, the lamins are mobile, have an impact on the nuclear envelop structure, and may induce changes in their regulatory functions. Changes in the nuclear lamina shape cause changes in cellular functions. A quantitative description of these structural changes could provide an unbiased description of changes in cellular function. In this review, we describe how changes in the nuclear lamina can be measured from three-dimensional images of lamins at the nuclear envelope, and we discuss how structural changes of the nuclear lamina can be used for cell classification.
    Type of Medium: Online Resource
    ISSN: 2090-7907
    URL: Article
    DOI: 10.1155/2013/374385
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2013
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  • 3
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    DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells
    Elsevier BV ; 2017
    In:  Cell Reports Vol. 20, No. 1 ( 2017-07), p. 61-75
    Details
    In: Cell Reports, Elsevier BV, Vol. 20, No. 1 ( 2017-07), p. 61-75
    Type of Medium: Online Resource
    ISSN: 2211-1247
    URL: Article
    DOI: 10.1016/j.celrep.2017.06.020
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
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  • 4
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    Abstract 1478: Gene-selective recruitment of NuRD drives chromatin reprogramming in cancer cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1478-1478
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1478-1478
    Abstract: ATP-dependent chromatin remodelers are frequently mutated in cancers. However, the molecular basis of the association between mutations in specific remodeler subunits and particular types of cancer is poorly understood. To understand how remodelers are targeted in a cell-type specific manner, we aim to explore the mechanisms of the Nucleosome Remodeling and Deacetylase (NURD) complex during cancer progression. We recently showed that DOC1-dependent recruitment of NuRD reveals antagonism with SWI/SNF during epithelial-mesenchymal transition in oral cancer cells (Mohd-Sarip et al., 2017). It is instructive to compare the function of DOC1 in oral squamous cell carcinomas (OSCCs) with that of the SWI/SNF subunit SMARCB1/hSNF5 in malignant rhabdoid tumors (MRTs). MRTs are an extremely aggressive pediatric cancer caused by the loss of SMARCB1 (Kia et al., 2008). Although the loss of DOC1 in OSCCs or that of SMARCB1 in MRTs generates opposite epigenetic states of their target genes, in both cases, this is caused by failed remodeler recruitment. The loss of a single subunit, such as DOC1 or SMARCB1, does not abrogate all other remodeler functions. We suggest that subunit-dependent gene selection is a major cause of the association between the loss of specific remodeler subunits and particular types of cancer. Our results emphasize that gene control involves a dynamic equilibrium between opposing chromatin modulating enzymes rather than a static chromatin state. Disturbances in this balance can initiate a cascade of chromatin reprogramming events that drives oncogenesis. Such an intertwined system of epigenetic regulation suggests therapeutic strategies aimed at restoring the balance between antagonistic activities. Prompted by these findings, we will present an inclusive view of the protein regulatory network in order to gain a wholesome understanding of the molecular transactions and dynamic composition of NuRD complexes in specific cancer types. These were identified by immunopurifications using in-house antibodies followed by mass spectrometry. Our proteomic studies of the NuRD complex in flies (Reddy et al., 2010) and HeLa nuclear extracts suggest that mammalian NuRD share the same subunits with flies. Upon closer inspection, we found unanticipated novel interacting partners of NuRD and that they are altered in specific cancers namely prostate, pancreatic and ovarian. This will be followed by confirmation of the interactomes using cell-based and biochemistry assays in combination with genome-wide approaches, as well as potentially leading to the characterization of novel targets of NuRD. These findings will represent the types of multiprotein NuRD-like complexes that can form during cancer progression and how they are targeted to chromatin. Citation Format: Adone Mohd-Sarip, Diana Zatreanu, Jeroen A. Demmers, C Peter Verrijzer. Gene-selective recruitment of NuRD drives chromatin reprogramming in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1478.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1478
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability
    Elsevier BV ; 2019
    In:  Molecular Cell Vol. 76, No. 1 ( 2019-10), p. 57-69.e9
    Details
    In: Molecular Cell, Elsevier BV, Vol. 76, No. 1 ( 2019-10), p. 57-69.e9
    Type of Medium: Online Resource
    ISSN: 1097-2765
    URL: Article
    DOI: 10.1016/j.molcel.2019.07.037
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2001948-8
    SSG: 12
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  • 6
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    Abstract P056: Polθ inhibitors elicit BRCA -gene synthetic lethality and target PARP inhibitor resistance
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 12_Supplement ( 2021-12-01), p. P056-P056
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 12_Supplement ( 2021-12-01), p. P056-P056
    Abstract: To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight, allosteric inhibitors of the polymerase function of DNA polymerase Theta (Polθ), including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous End Joining. Moreover, we show that exposure to ART558 can elicit DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which are a cause of PARP inhibitor resistance, result in in vitro and in vivo sensitivity to Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells. The inhibition of DNA nucleases that promote end-resection reversed these effects, suggesting that resection via Exo1 or Blm-Dna2 being a cause, at least in part, of the ART558 sensitivity phenotype. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance. Citation Format: Diana A. Zatreanu, Helen M. R. Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall M. B. Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luned M Badder, Daniela Novo, Eleanor G. Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Katherine Ewings, Andre Nussenzweig, Marcel Tijsterman, Andrew Tutt, Simon J. Boulton, Geoff S. Higgins, Steve Pettitt, Graeme C. M. Smith, Christopher J. Lord. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P056.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-21-P056
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    SSG: 12
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  • 7
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    Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability
    Elsevier BV ; 2018
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.3283710
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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  • 8
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    Resistance to DNA repair inhibitors in cancer
    Wiley ; 2022
    In:  Molecular Oncology Vol. 16, No. 21 ( 2022-11), p. 3811-3827
    Details
    In: Molecular Oncology, Wiley, Vol. 16, No. 21 ( 2022-11), p. 3811-3827
    Abstract: The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre‐clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polθ (Pol‐Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.v16.21
    DOI: 10.1002/1878-0261.13224
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 9
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    Abstract 5229: The mutually exclusive and diverse NuRD chromatin remodeling complex in cancer progression
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5229-5229
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5229-5229
    Abstract: Introduction: ATP-dependent chromatin remodelers are frequently mutated in cancers. Similar to the better studied SWI/SNF remodelers, the sequencing of cancer genomes has uncovered frequent mutations in genes encoding the Nucleosome remodeling and histone deacetylase (NuRD) subunits. Upon closer inspection, NuRD complex is highly amplified in breast cancer, deleted in prostate cancer, yet mutated in lung cancer. These observations suggest that (in)activation of NuRD might contribute to oncogenesis in a cell-type specific manner. Prompted by these findings, and to gain insights into the functions of the NuRD complex, we first need to understand the composition of this complex(es). Material & Methods: We carried out Immunoprecipitation (IP) with antibodies raised against NuRD members DOC1 and CHD4, followed by mass spectrometry (MS) with HeLa nuclear extracts. This was followed by ‘reverse’ IP-MS i.e. using antibodies raised against these novel NuRD-associated factors (AFs) on HeLa nuclear extracts and data mining for the NuRD-AFs (cBioPortal). Re-expression and knockdowns of DOC1, CHD4 and NuRD-AFs were executed in selected breast, prostate and lung carcinoma cell lines. High resolution MNase nucleosomal mapping followed by qPCR was performed at specific target loci. Results & Discussions: Proteomics data suggest that ZFHX3 (cancer determinant), ZBTB2 (developmental regulator) and SMAD4 (BMP/TGF-beta signalling pathway) as NuRD-AFs. Interestingly, DOC1 IP reveals interaction only with SMAD4 while CHD4 immunoprecipitation uncovered interaction only with ZFHX3. Besides, ZBTB2 associated with both DOC1 and CHD4-NuRD. It is worth noting that these novel NuRD-AFs were found to be frequently altered in specific cancers e.g. prostate, non-small cell lung and breast carcinomas. Re-expression and knockdowns of NuRD-AFs affected epithelial-mesenchymal transitions (EMT) and chromatin dynamics during cancer progression. Conclusion: Remodeling of chromatin is an essential step towards gene expression, therefore in order to study the critical role of NuRD-AFs during carcinogenesis, a higher resolution picture of the dynamic changes in chromatin and nucleosomal structure is pertinent. These mapping experiments revealed nucleosome occupancy as well as (in)accessibility of chromatin during carcinogenesis, in particular at specific target loci. Chromatin dynamics uncovered in specific carcinoma cell lines thereby generating a comprehensive picture of the various chromatin states during carcinogenesis and expanding our understanding of chromatin function. The impact will be protein/gene expression as well as chromatin (in)accessibility and structure could be used in (early) diagnostics and prediction of carcinogenesis or biomarker discovery, in combination with already available diagnostics/biomarkers; towards a more targeted and personalised therapy for cancer patients. Note: This abstract was not presented at the meeting. Citation Format: Adone Mohd-Sarip, Diana Zatreanu, Jeroen Demmers. The mutually exclusive and diverse NuRD chromatin remodeling complex in cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5229.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-5229
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 5697: Targeting PARP inhibitor resistance with Polθ inhibitors
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5697-5697
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5697-5697
    Abstract: To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous End Joining. Moreover, we show that exposure to ART558 can elicit DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumor cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which are a cause of PARP inhibitor resistance, result in in vitro and in vivo sensitivity to Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells. The inhibition of DNA nucleases that promote end-resection, such as Exo1 or Blm-Dna2 reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance. Citation Format: Diana Zatreanu, Helen Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luted Badder, Daniela Novo, Eleanor Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Andre Nussenzweig, Marcel Tijsterman, Andrew N. Tutt, Simon Boulton, Geoff Higgins, Stephen J. Pettitt, Graeme C. Smith, Christopher J. Lord. Targeting PARP inhibitor resistance with Polθ inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5697.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5697
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 410466-3
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