Journal article

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

Jordan R Becker, Raquel Cuella-Martin, Marco Barazas, Rui Liu, Catarina Oliveira, Antony W Oliver, Kirstin Bilham, Abbey B Holt, Andrew N Blackford, Jorg Heierhorst, Jos Jonkers, Sven Rottenberg, J Ross Chapman



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 ..

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Awarded by Cancer Research UK Career Development Fellowship (CRUK CDF)

Awarded by CRUK CDF

Awarded by CRUK grant

Awarded by Worldwide Cancer Research

Awarded by National Health and Medical Research Council of Australia

Awarded by Dutch Cancer Society

Awarded by Netherlands Organization for Scientific Research

Awarded by Swiss National Science Foundation

Awarded by Swiss Cancer League

Awarded by European Union

Awarded by Wellcome

Awarded by MRC

Funding Acknowledgements

This study was funded by Cancer Research UK Career Development Fellowship (CRUK CDF; C52690/A19270) awarded to J.R.C., that provides salary support for C.O. and J.R.B.; a Nuffield Department of Medicine Prize DPhil studentship to R.C.M.; CRUK CDF funding to ANB (C29215/A20772); CRUK grant (C302/A24386) to AWO; grants from Worldwide Cancer Research (WCR 16-0156) and the National Health and Medical Research Council of Australia (NHMRC 1139099) to JH; financial support also came from the Dutch Cancer Society (KWF 2014-6532 to S.R. and J.J.), the Netherlands Organization for Scientific Research (VICI 91814643, NGI 93512009, Cancer Genomics Netherlands and a National Roadmap grant for Large-Scale Research Facilities to J.J.), the Swiss National Science Foundation (310030_ 156869 to S.R.), the Swiss Cancer League (KLS-4282-08-2017 to S.R.), and the European Union (ERC StG 311565 to J.J.L.J., ERC CoG-681572 to S.R.). The Wellcome Centre for Human Genetics is supported by Wellcome core award 090532/Z/09/Z. St. Vincent's Institute of Medical Research is supported by NHMRC Independent Research Institutes Infrastructure Support and Victorian State Government Operational Infrastructure Support grants. The authors thank A. Nussenzweig and E. Callen-Moreau for advice/reagents, S. Snellenberg for cell-cycle lysates, and all laboratory members for discussions and critique. We also thank C. Green (Chromosome Dynamics core) for expertise and assistance with FRAP experiments. We thank D. Durocher and D. Chowdhury for discussing unpublished results, and credit D. Durocher and S. Noordermeer for sharing DYNLL1-targeting CRISPR reagents and for initiating the mouse tumour studies with S.R. and J.J.