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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. BRCA1RNF168cells 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.

Pubmed ID: 30704900 RIS Download

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This is a list of tools and resources that we have found mentioned in this publication.

Monoclonal ANTI-FLAG® M2 antibody (antibody)


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Rad51 (H-92) antibody (antibody)


This polyclonal antibody targets Rad51 (H-92)

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RPA32 (4E4) Rat mAb antibody (antibody)


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BrdU antibody [BU1/75 (ICR1)] (antibody)


This monoclonal antibody targets BrdU antibody [BU1/75 (ICR1)]

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53BP1 Antibody (antibody)


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DEPDC1B-human antibody (antibody)


This unknown targets DEPDC1B

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CENPF antibody (antibody)


This polyclonal antibody targets CENPF

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This polyclonal antibody targets PALB2

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Monoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)


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Phospho RPA32 (S4/S8) Antibody (antibody)


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NEW Anti-RNF168 antibody (antibody)


This polyclonal antibody targets NEW RNF168

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gamma H2AX Antibody (antibody)


This unknown targets gamma H2AX

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BOSC-23 (cell line)


Cell line BOSC-23 is aTransformed cell line with a species of origin Homo sapiens

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