Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation

Wenjun Liu, Guanying Wang, Anna Palovcak, Yan Li, Sophie Hao, Zhao Jun Liu, Ralf Landgraf, Fenghua Yuan, Yanbin Zhang

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)10-17
Number of pages8
JournalDNA Repair
Volume77
DOIs
StatePublished - May 1 2019

Fingerprint

Double-Stranded DNA Breaks
Repair
Annealing
Degradation
Fanconi Anemia Complementation Group A Protein
DNA
Down-Regulation
Fanconi Anemia
Defects
Mitomycin
Lactones
Proteasome Endopeptidase Complex
withaferin A
Cells

Keywords

  • Double strand break repair
  • FANCA
  • Fanconi anemia
  • Single strand annealing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation. / Liu, Wenjun; Wang, Guanying; Palovcak, Anna; Li, Yan; Hao, Sophie; Liu, Zhao Jun; Landgraf, Ralf; Yuan, Fenghua; Zhang, Yanbin.

In: DNA Repair, Vol. 77, 01.05.2019, p. 10-17.

Research output: Contribution to journalArticle

Liu, Wenjun ; Wang, Guanying ; Palovcak, Anna ; Li, Yan ; Hao, Sophie ; Liu, Zhao Jun ; Landgraf, Ralf ; Yuan, Fenghua ; Zhang, Yanbin. / Impeding the single-strand annealing pathway of DNA double-strand break repair by withaferin A-mediated FANCA degradation. In: DNA Repair. 2019 ; Vol. 77. pp. 10-17.
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AU - Palovcak, Anna

AU - Li, Yan

AU - Hao, Sophie

AU - Liu, Zhao Jun

AU - Landgraf, Ralf

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AU - Zhang, Yanbin

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