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USP14 is a deubiquitinase for Ku70 and critical determinant of non-homologous end joining repair in autophagy and PTEN-deficient cells

Sharma, Arishya, Alswillah, Turkeya, Kapoor, Isha, Debjani, Pal, Willard, Belinda, Summers, Matthew K, Gong, Zihua, Almasan, Alexandru·2019·Nucleic Acids Research
DOI 10.1093/nar/gkz1103PMC PMC7145659
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Abstract

Ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are predominantly repaired by non-homologous end joining (NHEJ). IR-induced DNA damage activates autophagy, an intracellular degradation process that delivers cytoplasmic components to the lysosome. We identified the deubiquitinase USP14 as a novel autophagy substrate and a regulator of IR-induced DNA damage response (DDR) signaling. Inhibition of autophagy increased levels and DSB recruitment of USP14. USP14 antagonized RNF168-dependent ubiquitin signaling and downstream 53BP1 chromatin recruitment. Here we show that autophagy-deficient cells are defective in NHEJ, as indicated by decreased IR-induced foci (IRIF) formation by pS2056-, pT2609-DNA-PKcs, pS1778-53BP1, RIF1 and a reporter assay activation. Moreover, chromatin recruitment of key NHEJ proteins, including, Ku70, Ku80, DNA-PKcs and XLF was diminished in autophagy-deficient cells. USP14 inhibition rescued the activity of NHEJ-DDR proteins in autophagy-deficient cells. Mass spectrometric analysis identified USP14 interaction with core NHEJ proteins, including Ku70, which was validated by co-immunoprecipitation. An in vitro assay revealed that USP14 targeted Ku70 for deubiquitination. AKT, which mediates Ser432-USP14 phosphorylation, was required for IRIF formation by USP14. Similar to USP14 block, AKT inhibition rescued the activity of NHEJ-DDR proteins in autophagy- and PTEN-deficient cells. These findings reveal a novel negative PTEN/Akt-dependent regulation of NHEJ by USP14.

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Figure 1. Increased USP14 chromatin recruitment in shATG7-inducible cells. (A) Diagram of pINDUCER-shATG7 system. pINDUCER-shATG7 encodes a constitutive cassette (rtTA3 and eGFP) and an inducible transcript (shATG7 and tRFP). (B) Fluorescence microscopy images of pINDUCER –shATG7-expressing (shATG7-inducible) LNCaP cells in the presence or absence of 800 ng/ml doxycycline (dox) for 72 h showing GFP and RFP expression. (C) Western blot analysis for ATG7 in shATG7-inducible LNCaP cells following indicated treatments. β-actin was used as the loading control. (D) Chromatin recruitment of USP14, RNF168, 53BP1, and H4 in shATG7-inducible LNCaP cells following dox ± 4 Gy IR. (E) Representative confocal images and (F) quantification of USP14 IRIFs at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox for 72 h, and preincubated with 50 μM IU1 for 1 h prior to 4 Gy IR treatment. Nuclei were stained with DAPI. Statistical significance was determined using Student's t-test and two-way Anova (n = 3). P < 0.01*, P < 0.001**, P < 0.0001***.
Figure 1. Increased USP14 chromatin recruitment in shATG7-inducible cells. (A) Diagram of pINDUCER-shATG7 system. pINDUCER-shATG7 encodes a constitutive cassette (rtTA3 and eGFP) and an inducible transcript (shATG7 and tRFP). (B) Fluorescence microscopy images of pINDUCER –shATG7-expressing (shATG7-inducible) LNCaP cells in the presence or absence of 800 ng/ml doxycycline (dox) for 72 h showing GFP and RFP expression. (C) Western blot analysis for ATG7 in shATG7-inducible LNCaP cells following indicated treatments. β-actin was used as the loading control. (D) Chromatin recruitment of USP14, RNF168, 53BP1, and H4 in shATG7-inducible LNCaP cells following dox ± 4 Gy IR. (E) Representative confocal images and (F) quantification of USP14 IRIFs at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox for 72 h, and preincubated with 50 μM IU1 for 1 h prior to 4 Gy IR treatment. Nuclei were stained with DAPI. Statistical significance was determined using Student's t-test and two-way Anova (n = 3). P < 0.01*, P < 0.001**, P < 0.0001***.CC BY · PubMed Central
Figure 2. USP14 inhibits DDR signaling in shATG7-inducible cells. Confocal immunostaining and graphical representation of IRIFs for (A, B) γ-H2AX, (C, D) RNF168, (E, F) 53BP1, and (G, H) RIF1 at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox for 72 h, and preincubated with 50 μM IU1 for 1 h prior to 4 Gy IR treatment. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01**.
Figure 2. USP14 inhibits DDR signaling in shATG7-inducible cells. Confocal immunostaining and graphical representation of IRIFs for (A, B) γ-H2AX, (C, D) RNF168, (E, F) 53BP1, and (G, H) RIF1 at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox for 72 h, and preincubated with 50 μM IU1 for 1 h prior to 4 Gy IR treatment. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01**.CC BY · PubMed Central
Figure 3. USP14 disrupts NHEJ DDR in autophagy-deficient cells. (A) Chromatin recruitment of the indicated proteins in shATG7-inducible LNCaP cells following +/- dox +/- IU1 +/- 4Gy IR at the indicated time points. H4 was used as loading control for the chromatin-bound fraction. (B) NHEJ measured by a plasmid luciferase repair assay in shCtrl- versus shUSP14-expressing C4-2 cells. Nu7441 treatment in shCtrl-expressing C4-2 cells was used as a negative control. Data are normalized for transfection efficiency and then to uncut luciferase. Confocal immunostaining and graphical representation of quantitation of (C, D) DNA-PKCs-T2609, (E, F) DNA-PKCs-S2056, (G, H) 53BP1-S1778 IRIFs at the indicated time points in shATG7-inducible LNCaP cells following ± dox ± IU1 ±± 4Gy IR. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01**.
Figure 3. USP14 disrupts NHEJ DDR in autophagy-deficient cells. (A) Chromatin recruitment of the indicated proteins in shATG7-inducible LNCaP cells following +/- dox +/- IU1 +/- 4Gy IR at the indicated time points. H4 was used as loading control for the chromatin-bound fraction. (B) NHEJ measured by a plasmid luciferase repair assay in shCtrl- versus shUSP14-expressing C4-2 cells. Nu7441 treatment in shCtrl-expressing C4-2 cells was used as a negative control. Data are normalized for transfection efficiency and then to uncut luciferase. Confocal immunostaining and graphical representation of quantitation of (C, D) DNA-PKCs-T2609, (E, F) DNA-PKCs-S2056, (G, H) 53BP1-S1778 IRIFs at the indicated time points in shATG7-inducible LNCaP cells following ± dox ± IU1 ±± 4Gy IR. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01**.CC BY · PubMed Central
Figure 4. Constitutive Akt regulates USP14 IRIF and NHEJ DDR signaling in autophagy-deficient cells. Confocal immunostaining and graphical representation of (A, B) USP14, (C, D) DNA-PKCs-S2056IRIF at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox and preincubated with 10 μM MK2206 for 1 h prior to the 4Gy IR treatment. LNCaP cells were transfected with GFP-PTEN, (E, F) 53BP1 and (G, H) DNA-PKcs S2056 IRIF formation were analyzed in PTEN+ vs. PTEN- cells, following indicated treatments. C4-2 cells were transfected with GFP-PTEN, and (I, J) 53BP1 and (K, L) DNA-PKcs S2056 IRIF formation were analyzed in PTEN+ versus PTEN- cells, following indicated treatments. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01 **.
Figure 4. Constitutive Akt regulates USP14 IRIF and NHEJ DDR signaling in autophagy-deficient cells. Confocal immunostaining and graphical representation of (A, B) USP14, (C, D) DNA-PKCs-S2056IRIF at the indicated time points in shATG7-inducible LNCaP cells that were treated with dox and preincubated with 10 μM MK2206 for 1 h prior to the 4Gy IR treatment. LNCaP cells were transfected with GFP-PTEN, (E, F) 53BP1 and (G, H) DNA-PKcs S2056 IRIF formation were analyzed in PTEN+ vs. PTEN- cells, following indicated treatments. C4-2 cells were transfected with GFP-PTEN, and (I, J) 53BP1 and (K, L) DNA-PKcs S2056 IRIF formation were analyzed in PTEN+ versus PTEN- cells, following indicated treatments. Nuclei were stained with DAPI. Data shown are the means ± SEM (n = 2); P < 0.05 *, P < 0.01 **.CC BY · PubMed Central
Figure 5. USP14 directly interacts with Ku70 and targets its ubiquitination. (A) List of NHEJ associated proteins that were found to interact with USP14 using Mass spectrometric analysis. (B) HEK 293T cells were transfected with the indicated constructs, followed by immunoprecipitation using anti-HA antibody and immunoblotting using the indicated antibodies. The corresponding whole cell lysates (WCLs) were used as input controls and probed with the indicated antibodies. (C) LNCaP cells were treated with 4 Gy IR, as indicated, and USP14 was immunoprecipitated followed by immunoblotting against indicated antibodies. (D) HEK 293T cells were transfected with His-Ub and Flag-KU70, followed by MG132 and 10 Gy IR treatment. Cells were lysed under denaturing conditions, followed by immunoprecipitation of Flag-KU70 and incubation either with or without recombinant USP14. Eluted samples were separated on SDS-PAGE and immunoblotted as indicated. (E) Quantitative representation of Ku70-Ub determined in D. (F) Western blot analysis for Ku70 and USP14 at the indicated times following 4 Gy IR treatment in C4-2 cells stably expressing shCtrl or shUSP14, β-actin was used as the loading control. (G) Chromatin recruitment of Ku70 in LNCaP cells following IU1 ± 4Gy IR treatments at the indicated time points. H2A was used as loading control for the chromatin-bound fractions.
Figure 5. USP14 directly interacts with Ku70 and targets its ubiquitination. (A) List of NHEJ associated proteins that were found to interact with USP14 using Mass spectrometric analysis. (B) HEK 293T cells were transfected with the indicated constructs, followed by immunoprecipitation using anti-HA antibody and immunoblotting using the indicated antibodies. The corresponding whole cell lysates (WCLs) were used as input controls and probed with the indicated antibodies. (C) LNCaP cells were treated with 4 Gy IR, as indicated, and USP14 was immunoprecipitated followed by immunoblotting against indicated antibodies. (D) HEK 293T cells were transfected with His-Ub and Flag-KU70, followed by MG132 and 10 Gy IR treatment. Cells were lysed under denaturing conditions, followed by immunoprecipitation of Flag-KU70 and incubation either with or without recombinant USP14. Eluted samples were separated on SDS-PAGE and immunoblotted as indicated. (E) Quantitative representation of Ku70-Ub determined in D. (F) Western blot analysis for Ku70 and USP14 at the indicated times following 4 Gy IR treatment in C4-2 cells stably expressing shCtrl or shUSP14, β-actin was used as the loading control. (G) Chromatin recruitment of Ku70 in LNCaP cells following IU1 ± 4Gy IR treatments at the indicated time points. H2A was used as loading control for the chromatin-bound fractions.CC BY · PubMed Central

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Metadata

Authors
Sharma, A., Alswillah, T., Kapoor, I., Debjani, P., Willard, B., Summers, M. K., Gong, Z., & Almasan, A.
Affiliations
  • Department of Cancer Biology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
  • Department of Radiation Oncology and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43017, USA
  • Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2019-11-19
ISSN
  • 0305-1048
  • 1362-4962
DOI
10.1093/nar/gkz1103
PMC
PMC7145659
Cited by
15
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institutes of Health (P30CA043703, 1S10OD019972-01, 1S10RR026820-01)
  • Mass Spectrometry the Orbitrap Elite instrument (1S10RR031537-01, CA184137, CA222195, GM112895)

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CoChat. (2026). Citation check: USP14 is a deubiquitinase for Ku70 and critical determinant of non-homologous end joining repair in autophagy and PTEN-deficient cells. https://app.cochat.ai/papers/10.1093/nar/gkz1103
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Sharma, A., Alswillah, T., Kapoor, I., Debjani, P., Willard, B., Summers, M. K., Gong, Z., & Almasan, A. (2019). USP14 is a deubiquitinase for Ku70 and critical determinant of non-homologous end joining repair in autophagy and PTEN-deficient cells. Nucleic Acids Research. https://doi.org/10.1093/nar/gkz1103