Valosin-containing protein regulates the proteasome-mediated degradation of DNA-PKcs in glioma cells

Jiang, Na; Shen, Yifeng; Fei, X; Sheng, Kuo Ching; Sun, Pengfei; Qiu, Yongming; Larner, James M.; Cao, Lichun; Kong, Xiangying; Mi, Jun

doi:10.1038/cddis.2013.171

Cited by 33 publications

(35 citation statements)

References 44 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VCP is a member of the AAA class of ATPases, found predominantly in the cytoplasm, and involved in diverse biological processes, including endoplasmic reticulumassociated degradation and ubiquitin fusion degradation (47). Knockdown of VCP in glioblastoma cells led to accumulation of DNA-PKcs and resistance to ionizing irradiation, ultimately resulting in shorter survival times in an orthotopic xenograft mouse model (46). This study supports the importance of regulation of DNA-PKcs ubiquitination in the cytoplasm.…”

Section: Discussionsupporting

confidence: 69%

“…Additional experiments will be needed to address these interesting questions. During our manuscript preparation, Jiang et al (46) showed that DNA-PKcs is ubiquitinated and bound to valosincontaining protein (VCP), possibly for regulation of proteasomedependent degradation. VCP is a member of the AAA class of ATPases, found predominantly in the cytoplasm, and involved in diverse biological processes, including endoplasmic reticulumassociated degradation and ubiquitin fusion degradation (47).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Ho¹,

Mahanic

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNAPKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner. RNF144A is mainly localized in the cytoplasmic vesicles and plasma membrane and interacts with cytoplasmic DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). DNA-PKcs plays a critical role in the nonhomologous end-joining DNA repair pathway and provides prosurvival signaling during DNA damage. We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. Depletion of RNF144A leads to an increased level of DNA-PKcs and resistance to DNA damaging agents, which is reversed by a DNA-PK inhibitor. Taken together, our data suggest that RNF144A may be involved in p53-mediated apoptosis through down-regulation of DNA-PKcs when cells suffer from persistent or severe DNA damage insults.endosome | DDR | transmembrane domain R ing Finger protein 144A (RNF144A) and RNF144B belong to the RNF144 family and are very conserved in higher eukaryotes. Both proteins contain an RING1-in between rings (IBR) -RING2 [termed the ring between ring fingers (RBR)] domain in the N terminus and a potential single-transmembrane (TM) domain in the C terminus. RBR domain-containing proteins usually possess an E3 ubiquitin ligase activity and are involved in regulation of the cell cycle and apoptosis (1-3). These proteins function like RING (Really Interesting New Gene)/HECT (Homologous to the E6AP Carboxyl Terminus) hybrids (i.e., they use their RING1 to bind E2s) but then transfer ubiquitin onto a conserved cysteine residue in the RING2 domain through a thioester linkage similar to the E3 thioester-linked ubiquitin intermediates in HECT-type E3 ligases (4). It has been shown that DNA damage induces RNF144B expression to promote cell apoptosis through regulation of the stability of p21 (5), BAX (1), and p73 (6). RNF144B shares 71% homology of amino acids with RNF144A.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Ho¹,

Mahanic

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…hDAAO‐EYFP; Fig. B) suggesting that it enhances degradation processes mediated by the UPS in a compensatory way, as previously reported for different proteins . An increasing body of evidence suggests that cross‐talk between the UPS and the lysosome system does exist and consists of a sharing of some of the ubiquitin‐recognizing molecules or shuttle factors: cells respond to blockage of the UPS by up‐regulating macroautophagy, whereas a persistent halt of macroautophagy has been shown to affect UPS activity .…”

Section: Discussionmentioning

confidence: 90%

The degradation (by distinct pathways) of human d‐amino acid oxidase and its interacting partner pLG72 – two key proteins in d‐serine catabolism in the brain

et al. 2013

View full text Add to dashboard Cite

Human D-amino acid oxidase (EC 1.4.3.3; hDAAO) is a peroxisomal flavoenzyme significantly enriched in the mammalian brain. hDAAO has been proposed to play (with serine racemase; EC 5.1.1.18) an essential role in the catabolism of D-serine, an 'atypical' key signalling molecule that acts as allosteric activator of the N-methyl-D-aspartate-type glutamate receptor (NMDAr). hDAAO and its interacting partner pLG72 have been related to schizophrenia, a highly disabling psychiatric disorder in which a dysfunction of NMDA-mediated neurotransmission is widely assumed to occur. We previously demonstrated that the D-serine cellular concentration depends on hDAAO and pLG72 expression levels and that newly-synthesized hDAAO interacts with its modulator in the cytosol, being progressively destabilized and inactivated. To obtain insight into the mechanisms regulating cellular D-serine levels, we investigated the degradation pathways of hDAAO and pLG72 in U87 glioblastoma cells stably expressing enhanced yellow fluorescent protein-hDAAO (peroxisomal), hDAAO-enhanced yellow fluorescent protein (cytosolic) or pLG72-enhanced cyan fluorescent protein (mitochondrial) proteins. hDAAO is a long-lived protein: the peroxisomal fraction of this flavoprotein is degraded via the lysosomal/endosomal pathway (and blocking this pathway increases the cellular hDAAO activity and decreases D-serine levels), whereas the cytosolic portion is ubiquitinated and targeted to the proteasome. By contrast, pLG72 shows a rapid turnover (t 1/2 % 25-40 min) and is degraded via the proteasome system, albeit not ubiquitinated. Overexpression of pLG72 increases the turnover of hDAAO, in turn playing a protective role against excessive D-serine depletion.

show abstract

“…Recruited by the heterodimer of Ku70/Ku80 to DSBs, DNA-PKc (DNA-dependent protein kinase, catalytic subunit) phosphorylates and alters the activity of many proteins, including itself, to mediate DNA repair through the NHEJ pathway (16). Like most other eukaryotic intracellular proteins, both Ku70 (17) and DNA-PKc (18) are degraded via the ubiquitin-proteasome system, in which proteins are tagged by ubiquitin and then degraded by the 26S proteasome complex. In pertinent studies, the proteasome inhibitor MG132 significantly prolonged the half-lives of those DNA repair proteins in cultured cells.…”

mentioning

confidence: 99%

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

et al. 2017

View full text Add to dashboard Cite

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

show abstract

Valosin-containing protein regulates the proteasome-mediated degradation of DNA-PKcs in glioma cells

Cited by 33 publications

References 44 publications

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

The degradation (by distinct pathways) of human d‐amino acid oxidase and its interacting partner pLG72 – two key proteins in d‐serine catabolism in the brain

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

Contact Info

Product

Resources

About