Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin

Watson P. Folk, Alpana Kumari, Tetsushi Iwasaki, Slovénie Pyndiah, Joanna C. Johnson, Erica K. Cassimere, Amy L. Abdulovic-Cui, Daitoku Sakamuro

Research output: Contribution to journalArticle

Abstract

The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNAdamaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.

Original languageEnglish (US)
Pages (from-to)5700-5719
Number of pages20
JournalJournal of Biological Chemistry
Volume294
Issue number14
DOIs
StatePublished - Jan 1 2019

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Ataxia Telangiectasia
Nuclear Proteins
Cisplatin
Tumors
Phosphotransferases
Chemical activation
Cells
Neoplasms
Adenosine Diphosphate
E2F1 Transcription Factor
Curbs
Co-Repressor Proteins
Phosphorylation
Protein-Serine-Threonine Kinases
DNA
DNA-Binding Proteins
Biomarkers
Histones
DNA Damage
Cell Cycle

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin. / Folk, Watson P.; Kumari, Alpana; Iwasaki, Tetsushi; Pyndiah, Slovénie; Johnson, Joanna C.; Cassimere, Erica K.; Abdulovic-Cui, Amy L.; Sakamuro, Daitoku.

In: Journal of Biological Chemistry, Vol. 294, No. 14, 01.01.2019, p. 5700-5719.

Research output: Contribution to journalArticle

Folk, Watson P. ; Kumari, Alpana ; Iwasaki, Tetsushi ; Pyndiah, Slovénie ; Johnson, Joanna C. ; Cassimere, Erica K. ; Abdulovic-Cui, Amy L. ; Sakamuro, Daitoku. / Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 14. pp. 5700-5719.
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AU - Iwasaki, Tetsushi

AU - Pyndiah, Slovénie

AU - Johnson, Joanna C.

AU - Cassimere, Erica K.

AU - Abdulovic-Cui, Amy L.

AU - Sakamuro, Daitoku

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