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Nat Commun. 2018 Dec 17;9(1):5406. doi: 10.1038/s41467-018-07855-x.

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

Author information

1
Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
2
Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
3
St. Vincent's Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
4
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, UK.
5
MRC Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford, OX1 3TH, UK.
6
Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
7
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
8
Department of Medicine at St. Vincent's Hospital, Melbourne Medical School, The University of Melbourne, Fitzroy, VIC, 3065, Australia.
9
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, 3012, Switzerland.
10
Genome Integrity Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. rchapman@well.ox.ac.uk.

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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