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

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 BRCA...

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Vydáno v:	Nature communications Ročník 9; číslo 1; s. 5406 - 12
Hlavní autoři:	Becker, Jordan R., Cuella-Martin, Raquel, Barazas, Marco, Liu, Rui, Oliveira, Catarina, Oliver, Antony W., Bilham, Kirstin, Holt, Abbey B., Blackford, Andrew N., Heierhorst, Jörg, Jonkers, Jos, Rottenberg, Sven, Chapman, J. Ross
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 17.12.2018 Nature Publishing Group Nature Portfolio
Témata:	13/1 13/106 13/109 13/31 14/19 14/35 38/23 42/41 631/337/1427/2122 631/337/1427/2190 631/337/1427/2191 82/80 82/83 Adaptive immunity Adenosine diphosphate Animals Antigens Binding BRCA1 protein BRCA1 Protein - genetics Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer Cell Line, Tumor Chromatin Class switching Clonal deletion CRISPR-Cas Systems Cytoplasmic Dyneins - metabolism Deoxyribonucleic acid Dimerization DNA DNA Breaks, Double-Stranded DNA damage DNA End-Joining Repair - genetics Double-strand break repair Female Gene deletion Genomes Genomic instability Genomic Instability - genetics HEK293 Cells Homologous recombination Homology Humanities and Social Sciences Humans Immunity Immunoglobulins Inhibitors Localization MCF-7 Cells Mice Mice, Inbred C57BL Mice, Knockout multidisciplinary Mutation Non-homologous end joining Oligomerization Pathology Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Proteins Radiation Recruitment Ribose Science Science (multidisciplinary) Stability Targeted cancer therapy Transcription Transcription Factors - metabolism Tumor Suppressor p53-Binding Protein 1 - genetics
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. 53BP1 is a key player in non-homologous end joining (NHEJ). Here the authors reveal an important role for the multifunctional homodimeric protein hub dynein light chain 1 (DYNLL1) in increasing the efficacy of 53BP1-mediated repair of DNA double-strand breaks (DSBs) by NHEJ.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-07855-x