Interplay between BRCA1 and GADD45A and Its Potential for Nucleotide Excision Repair in Breast Cancer Pathogenesis

Int J Mol Sci. 2020 Jan 29;21(3):870. doi: 10.3390/ijms21030870.


A fraction of breast cancer cases are associated with mutations in the BRCA1 (BRCA1 DNA repair associated, breast cancer type 1 susceptibility protein) gene, whose mutated product may disrupt the repair of DNA double-strand breaks as BRCA1 is directly involved in the homologous recombination repair of such DNA damage. However, BRCA1 can stimulate nucleotide excision repair (NER), the most versatile system of DNA repair processing a broad spectrum of substrates and playing an important role in the maintenance of genome stability. NER removes carcinogenic adducts of diol-epoxy derivatives of benzo[α]pyrene that may play a role in breast cancer pathogenesis as their accumulation is observed in breast cancer patients. NER deficiency was postulated to be intrinsic in stage I of sporadic breast cancer. BRCA1 also interacts with GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) that may target NER machinery to actively demethylate genome sites in order to change the expression of genes that may be important in breast cancer. Therefore, the interaction between BRCA1 and GADD45 may play a role in breast cancer pathogenesis through the stimulation of NER, increasing the genomic stability, removing carcinogenic adducts, and the local active demethylation of genes important for cancer transformation.

Keywords: BRCA1; DNA demethylation; GADD45A; NER; breast cancer; nucleotide excision repair.

Publication types

  • Review

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • DNA Damage
  • DNA Methylation
  • DNA Repair*
  • Female
  • Genomic Instability
  • Humans
  • Tumor Suppressor Protein p53 / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • GADD45A protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53