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    The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity

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    Author
    Becker, JR; Cuella-Martin, R; Barazas, M; Liu, R; Oliveira, C; Oliver, AW; Bilham, K; Holt, AB; Blackford, AN; Heierhorst, J; ...
    Date
    2018-12-17
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Heierhorst, Jorg
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Becker, J. R., Cuella-Martin, R., Barazas, M., Liu, R., Oliveira, C., Oliver, A. W., Bilham, K., Holt, A. B., Blackford, A. N., Heierhorst, J., Jonkers, J., Rottenberg, S. & Chapman, J. R. (2018). The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-07855-x.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253381
    DOI
    10.1038/s41467-018-07855-x
    Abstract
    53BP1 controls a specialized non-homologous end joining (NHEJ) pathway that is essential for adaptive immunity, yet oncogenic in BRCA1 mutant cancers. Intra-chromosomal DNA double-strand break (DSB) joining events during immunoglobulin class switch recombination (CSR) require 53BP1. However, in BRCA1 mutant cells, 53BP1 blocks homologous recombination (HR) and promotes toxic NHEJ, resulting in genomic instability. Here, we identify the protein dimerization hub-DYNLL1-as an organizer of multimeric 53BP1 complexes. DYNLL1 binding stimulates 53BP1 oligomerization, and promotes 53BP1's recruitment to, and interaction with, DSB-associated chromatin. Consequently, DYNLL1 regulates 53BP1-dependent NHEJ: CSR is compromised upon deletion of Dynll1 or its transcriptional regulator Asciz, or by mutation of DYNLL1 binding motifs in 53BP1; furthermore, Brca1 mutant cells and tumours are rendered resistant to poly-ADP ribose polymerase (PARP) inhibitor treatments upon deletion of Dynll1 or Asciz. Thus, our results reveal a mechanism that regulates 53BP1-dependent NHEJ and the therapeutic response of BRCA1-deficient cancers.

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