+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation

Molecular Cell 2019

BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, and it predisposes BRCA1 heterozygous mice to cancer. BRCA1+/-RNF168-/- cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1 haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy for BRCA1-deficient cancers.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 066446956

Download citation: RISBibTeXText

PMID: 30704900

DOI: 10.1016/j.molcel.2018.12.010

Related references

Context Matters: RNF168 Connects with PALB2 to Rewire Homologous Recombination in BRCA1 Haploinsufficiency. Molecular Cell 73(6): 1089-1091, 2019

A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation. Elife 6, 2017

RNF168-mediated H2A neddylation antagonizes ubiquitylation of H2A and regulates DNA damage repair. Journal of Cell Science 127(Pt 10): 2238-2248, 2015

BRCA1-mediated ubiquitylation. Cell Cycle 5(14): 1481-1486, 2006

USP11 Is a Negative Regulator to γH2AX Ubiquitylation by RNF8/RNF168. Journal of Biological Chemistry 291(2): 959-967, 2016

RNF8 and RNF168 but not HERC2 are required for DNA damage-induced ubiquitylation in chicken DT40 cells. Dna Repair 11(11): 892-905, 2013

BRCA1 haploinsufficiency, but not heterozygosity for a BRCA1-truncating mutation, deregulates homologous recombination. Cell Cycle 6(8): 962-971, 2007

BRCA1 deficiency induces protective autophagy to mitigate stress and provides a mechanism for BRCA1 haploinsufficiency in tumorigenesis. Cancer Letters 346(1): 139-147, 2014

Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency. Genes, Chromosomes and Cancer 49(1): 78-90, 2010

Endocytosis of Ubiquitylation-Deficient EGFR Mutants via Clathrin-Coated Pits is Mediated by Ubiquitylation. Traffic 16(11): 1137-1154, 2016

BRCA1-mediated large-scale chromatin unfolding and transcriptional regulation. Breast Cancer Research & Treatment 76(Supplement 1): S124, 2002

An RNF168 fragment defective for focal accumulation at DNA damage is proficient for inhibition of homologous recombination in BRCA1 deficient cells. Nucleic Acids Research 42(12): 7720-7733, 2014

BRCA1-mediated chromatin silencing is limited to oocytes with a small number of asynapsed chromosomes. Journal of Cell Science 122(Pt 14): 2446-2452, 2009

RNF168, a new RING finger, MIU-containing protein that modifies chromatin by ubiquitination of histones H2A and H2AX. Bmc Molecular Biology 10: 55, 2009

Three-dimensional imaging reveals the spatial separation of γH2AX-MDC1-53BP1 and RNF8-RNF168-BRCA1-A complexes at ionizing radiation-induced foci. RadioTherapy and Oncology 103(3): 415-420, 2012