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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)

RRID:AB_262044

This monoclonal antibody targets FLAG

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Rad51 (H-92) antibody (antibody)

RRID:AB_2253533

This polyclonal antibody targets Rad51 (H-92)

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RPA32 (4E4) Rat mAb antibody (antibody)

RRID:AB_2238543

This monoclonal antibody targets RPA32

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

RRID:AB_305426

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

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53BP1 Antibody (antibody)

RRID:AB_10001695

This unknown targets 53BP1

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DEPDC1B-human antibody (antibody)

RRID:AB_1966097

This unknown targets DEPDC1B

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CENPF antibody (antibody)

RRID:AB_304721

This polyclonal antibody targets CENPF

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BrdU antibody (antibody)

RRID:AB_400326

This monoclonal antibody targets BrdU

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PALB2 Antibody (antibody)

RRID:AB_890608

This polyclonal antibody targets PALB2

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

RRID:AB_477579

This monoclonal antibody targets alpha-Tubulin antibody produced in mouse

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BRCA2 Antibody (antibody)

RRID:AB_10952240

This polyclonal antibody targets BRCA2

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Phospho RPA32 (S4/S8) Antibody (antibody)

RRID:AB_210547

This polyclonal antibody targets Phospho-RPA32 (Ser4, Ser8)

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NEW Anti-RNF168 antibody (antibody)

RRID:AB_11205761

This polyclonal antibody targets NEW RNF168

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gamma H2AX Antibody (antibody)

RRID:AB_10002815

This unknown targets gamma H2AX

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BOSC-23 (cell line)

RRID:CVCL_4401

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

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