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BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation

  1. Author:
    Zong, Dali
    Adam, Salome
    Wang, Yifan
    Sasanuma, Hiroyuki
    Callen, Elsa
    Murga, Matilde
    Day, Amanda
    Kruhlak, Michael J.
    Wong, Nancy
    Munro, Meagan
    Chaudhuri, Arnab Ray
    Karim,Baktiar
    Xia, Bing
    Takeda, Shunichi
    Johnson, Neil
    Durocher, Daniel
    Nussenzweig, Andre

  2. Author Address

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA.Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.Fox Chase Canc Ctr, Mol Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA.Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Kyoto, Japan.CNIO, Spanish Natl Canc Res Ctr, Genom Instabil Grp, Madrid, Spain.NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA.Erasmus Univ, Dept Mol Genet, Med Ctr, Rotterdam, Netherlands.Frederick Natl Lab Canc Res, Pathol Histotechnol Lab, Frederick, MD USA.Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA.Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
    1. Year: 2019
    2. Date: MAR 21
    3. Epub Date: 2019 01 10
  2. Journal: Molecular cell
  3. CELL PRESS,
    1. 73
    2. 6
    3. Pages: 1267-+
  5. Type of Article: Article
  6. ISSN: 1097-2765
  1. Abstract:

    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.

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External Sources

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  2. DOI: 10.1016/j.molcel.2018.12.010
  3. PMID: 30704900
  4. View record in Web of Science®
  5. WOS: 000462029500019

Library Notes

  1. Fiscal Year: FY2018-2019
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