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    On the mechanism of hyperthermia-induced BRCA2 protein degradation.

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    Authors
    van den Tempel, N
    Zelensky, AN
    Odijk, H
    Laffeber, C
    Schmidt, Christine K
    Brandsma, I
    Demmers, J
    Krawczyk, PM
    Kanaar, R
    Affiliation
    Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
    Issue Date
    2019
    
    Metadata
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    Abstract
    The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment-it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 -one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers.
    Citation
    van den Tempel N, Zelensky AN, Odijk H, Laffeber C, Schmidt CK, Brandsma I, et al. On the mechanism of hyperthermia-induced BRCA2 protein degradation. Cancers (Basel). 2019 Jan 15;11(1).
    Journal
    Cancers
    URI
    http://hdl.handle.net/10541/621613
    DOI
    10.3390/cancers11010097
    PubMed ID
    30650591
    Additional Links
    https://dx.doi.org/10.3390/cancers11010097
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.3390/cancers11010097
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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