Selective killing of homologous recombination-deficient cancer cell lines by inhibitors of the RPA:RAD52 protein-protein interaction.
Apoptosis
/ drug effects
BRCA1 Protein
/ deficiency
Cell Death
/ drug effects
Cell Line, Tumor
Cell Survival
/ drug effects
DNA Damage
DNA Repair
/ drug effects
Doxorubicin
/ pharmacology
Fluorescence
High-Throughput Screening Assays
Homologous Recombination
/ drug effects
Humans
Mitoxantrone
/ pharmacology
Neoplasms
/ metabolism
Protein Binding
/ drug effects
Quinacrine
/ pharmacology
Rad52 DNA Repair and Recombination Protein
/ metabolism
Replication Protein A
/ metabolism
Small Molecule Libraries
/ pharmacology
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
28
05
2020
accepted:
09
03
2021
entrez:
30
3
2021
pubmed:
31
3
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds.
Identifiants
pubmed: 33784323
doi: 10.1371/journal.pone.0248941
pii: PONE-D-20-16153
pmc: PMC8009417
doi:
Substances chimiques
BRCA1 Protein
0
Rad52 DNA Repair and Recombination Protein
0
Replication Protein A
0
Small Molecule Libraries
0
Doxorubicin
80168379AG
Mitoxantrone
BZ114NVM5P
Quinacrine
H0C805XYDE
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0248941Subventions
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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