CRL4-DCAF8L2 E3 ligase promotes ubiquitination and degradation of BARD1.

Abstract

BARD1 is a tumor suppressor that is necessary for the functioning and stability of BRCA1, with which it forms a heterodimer and participates in the repair of DNA double-strand breaks. The cellular level of BARD1 and its interaction with BRCA1 are crucial for BRCA1/BARD1 function in homologous recombination and tumor suppression. However, the regulatory mechanism underpinning the stability of BARD1 is largely unclear. In this study, we identified DCAF8L2, a DDB1-Cullin associated factor (DCAF) associated with CRL4 E3 ligase, as a negative regulator of BARD1. Mechanistically, DCAF8L2 interacts with and targets BARD1 for ubiquitination and degradation. In addition, the interaction of DCAF8L2 with BARD1 through the RING domain could compete with the dimerization of BRCA1 and BARD1, leading to increased cellular uncoupling of BARD1 and BRCA1, subjecting the latter to degradation. The overexpression of DCAF8L2 compromises the homologous recombination process and confers cells with increased sensitivity to DNA damage. Furthermore, DCAF8L2 was aberrantly expressed in breast cancer cell lines. Our findings suggest that DCAF8L2 may play an oncogenic role in the pathogenesis of breast cancer, possibly by negative regulation of BARD1.

• Authors: Jingcheng Deng, Ting Zhang, Fei Liu, Qianying Han, Qin Li, Xueyuan Guo, Yanfang Ma, Li Li, Genze Shao
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 611 Pg. 107-113 (06 30 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35487060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• BRCA1 Protein
• IL17RB protein, human
• Receptors, Interleukin-17
• Tumor Suppressor Proteins
• BARD1 protein, human
• Ubiquitin-Protein Ligases

Topics

• BRCA1 Protein (metabolism)
• Breast Neoplasms (metabolism)
• Female
• Homologous Recombination
• Humans
• Receptors, Interleukin-17 (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination