Department of Cell Biology, Peking University Health Science Center, Beijing, 100191, China.
Department of Cell Biology, Peking University Health Science Center, Beijing, 100191, China.
Biochem Biophys Res Commun. 2022 Jun 30;611:107-113. doi: 10.1016/j.bbrc.2022.04.100. Epub 2022 Apr 23.
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.
BARD1 是一种肿瘤抑制因子，对于 BRCA1 的功能和稳定性是必需的，它与 BRCA1 形成异二聚体，并参与 DNA 双链断裂的修复。BARD1 的细胞水平及其与 BRCA1 的相互作用对于 BRCA1/BARD1 在同源重组和肿瘤抑制中的功能至关重要。然而，BARD1 稳定性的调节机制在很大程度上尚不清楚。在这项研究中，我们鉴定了 DCAF8L2，一种与 DDB1-Cullin 相关的因子（DCAF），与 CRL4 E3 连接酶相关，是 BARD1 的负调控因子。在机制上，DCAF8L2 与 BARD1 相互作用，并将其靶向进行泛素化和降解。此外，DCAF8L2 通过 RING 结构域与 BARD1 的相互作用可以与 BRCA1 和 BARD1 的二聚化竞争，导致 BARD1 和 BRCA1 在细胞内解偶联增加，从而使后者降解。DCAF8L2 的过表达会损害同源重组过程，并使细胞对 DNA 损伤更加敏感。此外，DCAF8L2 在乳腺癌细胞系中异常表达。我们的研究结果表明，DCAF8L2 可能通过负调控 BARD1 在乳腺癌的发病机制中发挥致癌作用。
