TY - JOUR
T1 - Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin
AU - Folk, Watson P.
AU - Kumari, Alpana
AU - Iwasaki, Tetsushi
AU - Pyndiah, Slovénie
AU - Johnson, Joanna C.
AU - Cassimere, Erica K.
AU - Abdulovic-Cui, Amy L.
AU - Sakamuro, Daitoku
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grant R01CA140379, United States Army Department of Defense Prostate Can-cer Program DAMD 17-02-1-0131, and the first Georgia Cancer Center Polatty Award for Innovative Cancer Research (2018–2019) (to D.S.). D. S. holds a 1999 United States Patent with G. Prendergast, Patent No. 6,410,238, “Box-dependent Myc-interacting protein (Bin1) compositions and uses thereof” (The Wistar Institute of Anatomy and Biology, Philadel-phia, PA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
1 Recipient of a fellowship from Augusta University Graduate School (2014– 2015) and the R. August Roesel Memorial Award Research Excellence for Biochemistry and Cancer Biology (2016).
Publisher Copyright:
© 2019 Folk et al.
PY - 2019/4/5
Y1 - 2019/4/5
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.RA118.005699
DO - 10.1074/jbc.RA118.005699
M3 - Article
C2 - 30733337
AN - SCOPUS:85064394426
SN - 0021-9258
VL - 294
SP - 5700
EP - 5719
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -