Abstract
FANCA is a key player in the canonical Fanconi anemia (FA) repair pathway. We have recently shown that FANCA also plays an important role in the single-strand annealing sub-pathway (SSA) of DNA double-strand break (DSB) repair by biochemically catalyzing single-strand annealing. Here, we report that a steroidal lactone withaferin A (WA) specifically impedes SSA repair by promoting FANCA downregulation at a sub-micromolar concentration range. We find that WA causes FANCA downregulation post-translationally in a proteasome-dependent manner. This WA-mediated downregulation is achieved through HSP90 inhibition and disruption of the FANCA-HSP90 interaction. WA-mediated FANCA degradation significantly reduces cellular SSA repair, abolishes FANCD2 monoubiquitination, elevates sensitivity to mitomycin C, and results in accumulation of DSBs. Importantly, the WA-induced defect in SSA repair is highly dependent on the absence of FANCA protein and overexpression of exogenous WT-FANCA protein in WA-treated cells significantly complements the repair defect.
Original language | English (US) |
---|---|
Pages (from-to) | 10-17 |
Number of pages | 8 |
Journal | DNA Repair |
Volume | 77 |
DOIs | |
State | Published - May 2019 |
Keywords
- Double strand break repair
- FANCA
- Fanconi anemia
- Single strand annealing
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology