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

• DOI: 10.1038/s41467-018-07855-x
• Publication Date: 2018-12-14T16:15:37Z
• Authors: Jordan R. Becker; Raquel Cuella-Martin; Marco Barazas; Rui Liu; Catarina Oliveira; Antony W. Oliver; Kirstin Bilham; Abbey B. Holt; Andrew N. Blackford; Jörg Heierhorst; Jos Jonkers; Sven Rottenberg; J. Ross Chapman
• Keywords: PARP inhibitor

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) events during immunoglobulin class switch recombination (CSR) require 53BP1. However, cells, blocks homologous (HR) and promotes toxic NHEJ, resulting genomic instability. Here, we identify the protein dimerization hub-DYNLL1-as an organizer of multimeric complexes. DYNLL1 binding stimulates oligomerization, 53BP1's recruitment to, interaction with, DSB-associated chromatin. Consequently, regulates 53BP1-dependent NHEJ: CSR compromised upon deletion Dynll1 or its transcriptional regulator Asciz, by mutation motifs 53BP1; furthermore, Brca1 cells tumours are rendered resistant to poly-ADP ribose polymerase (PARP) inhibitor treatments Asciz. Thus, our results reveal mechanism NHEJ therapeutic response BRCA1-deficient