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@ARTICLE{Dueva:284758,
      author       = {R. Dueva and L. M. Krieger and F. Li and D. Luo and H. Xiao
                      and M. Stuschke$^*$ and E. Metzen and G. Iliakis},
      title        = {{C}hemical {I}nhibition of {RPA} by {HAMNO} {A}lters {C}ell
                      {C}ycle {D}ynamics by {I}mpeding {DNA} {R}eplication and
                      {G}2-to-{M} {T}ransition but {H}as {L}ittle {E}ffect on the
                      {R}adiation-{I}nduced {DNA} {D}amage {R}esponse.},
      journal      = {International journal of molecular sciences},
      volume       = {24},
      number       = {19},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2023-02069},
      pages        = {14941},
      year         = {2023},
      abstract     = {Replication protein A (RPA) is the major single-stranded
                      DNA (ssDNA) binding protein that is essential for DNA
                      replication and processing of DNA double-strand breaks
                      (DSBs) by homology-directed repair pathways. Recently, small
                      molecule inhibitors have been developed targeting the RPA70
                      subunit and preventing RPA interactions with ssDNA and
                      various DNA repair proteins. The rationale of this
                      development is the potential utility of such compounds as
                      cancer therapeutics, owing to their ability to inhibit DNA
                      replication that sustains tumor growth. Among these
                      compounds, (1Z)-1-[(2-hydroxyanilino) methylidene]
                      naphthalen-2-one (HAMNO) has been more extensively studied
                      and its efficacy against tumor growth was shown to arise
                      from the associated DNA replication stress. Here, we study
                      the effects of HAMNO on cells exposed to ionizing radiation
                      (IR), focusing on the effects on the DNA damage response and
                      the processing of DSBs and explore its potential as a
                      radiosensitizer. We show that HAMNO by itself slows down the
                      progression of cells through the cell cycle by dramatically
                      decreasing DNA synthesis. Notably, HAMNO also attenuates the
                      progression of G2-phase cells into mitosis by a mechanism
                      that remains to be elucidated. Furthermore, HAMNO increases
                      the fraction of chromatin-bound RPA in S-phase but not in
                      G2-phase cells and suppresses DSB repair by homologous
                      recombination. Despite these marked effects on the cell
                      cycle and the DNA damage response, radiosensitization could
                      neither be detected in exponentially growing cultures, nor
                      in cultures enriched in G2-phase cells. Our results
                      complement existing data on RPA inhibitors, specifically
                      HAMNO, and suggest that their antitumor activity by
                      replication stress induction may not extend to
                      radiosensitization. However, it may render cells more
                      vulnerable to other forms of DNA damaging agents through
                      synthetically lethal interactions, which requires further
                      investigation.},
      keywords     = {DNA double-strand break (Other) / DNA repair (Other) /
                      HAMNO (Other) / RPA (Other) / ionizing radiation (Other) /
                      replication (Other)},
      cin          = {ED01},
      ddc          = {540},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37834389},
      pmc          = {pmc:PMC10573259},
      doi          = {10.3390/ijms241914941},
      url          = {https://inrepo02.dkfz.de/record/284758},
}