Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors

Fei Huang, Nadish Goyal, Katherine Sullivan, Kritika Hanamshet, Mikir Patel, Olga M. Mazina, Charles X. Wang, W. Frank An, James Spoonamore, Shailesh Metkar, Kyle Allen Emmitte, Simon Cocklin, Tomasz Skorski, Alexander V. Mazin

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23 Citations (Scopus)

Abstract

RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1-and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair.

Original languageEnglish
Pages (from-to)4189-4199
Number of pages11
JournalNucleic Acids Research
Volume44
Issue number9
DOIs
StatePublished - 19 May 2016

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Mutation
Homologous Recombination
DNA Repair
Ovarian Neoplasms
Libraries
Mammals
Neoplasms
Fluorescence
Maintenance
Genome
Breast Neoplasms
Phenotype
DNA
Therapeutics
Growth
Genes
In Vitro Techniques

Cite this

Huang, F., Goyal, N., Sullivan, K., Hanamshet, K., Patel, M., Mazina, O. M., ... Mazin, A. V. (2016). Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors. Nucleic Acids Research, 44(9), 4189-4199. https://doi.org/10.1093/nar/gkw087
Huang, Fei ; Goyal, Nadish ; Sullivan, Katherine ; Hanamshet, Kritika ; Patel, Mikir ; Mazina, Olga M. ; Wang, Charles X. ; An, W. Frank ; Spoonamore, James ; Metkar, Shailesh ; Emmitte, Kyle Allen ; Cocklin, Simon ; Skorski, Tomasz ; Mazin, Alexander V. / Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors. In: Nucleic Acids Research. 2016 ; Vol. 44, No. 9. pp. 4189-4199.
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abstract = "RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1-and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair.",
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Huang, F, Goyal, N, Sullivan, K, Hanamshet, K, Patel, M, Mazina, OM, Wang, CX, An, WF, Spoonamore, J, Metkar, S, Emmitte, KA, Cocklin, S, Skorski, T & Mazin, AV 2016, 'Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors', Nucleic Acids Research, vol. 44, no. 9, pp. 4189-4199. https://doi.org/10.1093/nar/gkw087

Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors. / Huang, Fei; Goyal, Nadish; Sullivan, Katherine; Hanamshet, Kritika; Patel, Mikir; Mazina, Olga M.; Wang, Charles X.; An, W. Frank; Spoonamore, James; Metkar, Shailesh; Emmitte, Kyle Allen; Cocklin, Simon; Skorski, Tomasz; Mazin, Alexander V.

In: Nucleic Acids Research, Vol. 44, No. 9, 19.05.2016, p. 4189-4199.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors

AU - Huang, Fei

AU - Goyal, Nadish

AU - Sullivan, Katherine

AU - Hanamshet, Kritika

AU - Patel, Mikir

AU - Mazina, Olga M.

AU - Wang, Charles X.

AU - An, W. Frank

AU - Spoonamore, James

AU - Metkar, Shailesh

AU - Emmitte, Kyle Allen

AU - Cocklin, Simon

AU - Skorski, Tomasz

AU - Mazin, Alexander V.

PY - 2016/5/19

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AB - RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1-and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair.

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JF - Nucleic Acids Research

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Huang F, Goyal N, Sullivan K, Hanamshet K, Patel M, Mazina OM et al. Targeting BRCA1-and BRCA2-deficient cells with RAD52 small molecule inhibitors. Nucleic Acids Research. 2016 May 19;44(9):4189-4199. https://doi.org/10.1093/nar/gkw087