The BRCA1/BARD1 ubiquitin ligase and its substrates

Biochem J. 2021 Sep 30;478(18):3467-3483. doi: 10.1042/BCJ20200864.


Mutations in breast cancer type 1 susceptibility protein (BRCA1) and its heterodimeric binding partner BARD1 confer a high risk for the development of breast and ovarian cancers. The sole enzymatic function of the BRCA1/BARD1 complex is as a RING-type E3 ubiquitin (Ub) ligase, leading to the deposition of Ub signals onto a variety of substrate proteins. Distinct types of Ub signals deposited by BRCA1/BARD1 (i.e. degradative vs. non-degradative; mono-Ub vs. poly-Ub chains) on substrate proteins mediate aspects of its function in DNA double-stranded break repair, cell-cycle regulation, and transcriptional regulation. While cancer-predisposing mutations in both subunits lead to the inactivation of BRCA1/BARD1 ligase activity, controversy remains as to whether its Ub ligase activity directly inhibits tumorigenesis. Investigation of BRCA1/BARD1 substrates using rigorous, well-validated mutants and experimental systems will ultimately clarify the role of its ligase activity in cancer and possibly establish prognostic and diagnostic metrics for patients with mutations. In this review, we discuss the Ub ligase function of BRCA1/BARD1, highlighting experimental approaches, mechanistic considerations, and reagents that are useful in the study of substrate ubiquitylation. We also discuss the current understanding of two well-established BRCA1/BARD1 substrates (nucleosomal H2A and estrogen receptor α) and several recently discovered substrates (p50, NF2, Oct1, and LARP7). Lessons from the current body of work should provide a road map to researchers examining novel substrates and biological functions attributed to BRCA1/BARD1 Ub ligase activity.

Keywords: BARD1; BRCA1; ubiquitin ligases; ubiquitin signaling; ubiquitins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Histones
  • Neoplasm Proteins
  • Tumor Suppressor Proteins
  • Ubiquitin
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases