p8/nupr1 Regulates DNA-Repair Activity After Double-Strand Gamma Irradiation-Induced DNA Damage

INSERM U.624, Stress Cellulaire, Case 915, Parc Scientifique et Technologique de Luminy, Marseille Cedex 9, France.
Journal of Cellular Physiology (Impact Factor: 3.84). 12/2009; 221(3):594-602. DOI: 10.1002/jcp.21889
Source: PubMed


The stress protein p8 is a small, highly basic, unfolded, and multifunctional protein. We have previously shown that most of its functions are exerted through interactions with other proteins, whose activities are thereby enhanced or repressed. In this work we describe another example of such mechanism, by which p8 binds and negatively regulates MSL1, a histone acetyl transferase (HAT)-associated protein, which in turn binds the DNA-damage-associated 53BP1 protein to facilitate DNA repair following DNA gamma-irradiation. Contrary to the HAT-associated activity, MSL1-dependent DNA-repair activity is almost completely dependent on 53BP1 expression. The picture that has emerged from our findings is that 53BP1 could be a scaffold that gets the HAT MSL1-dependent DNA-repair activity to the sites of DNA damage. Finally, we also found that, although p8 expression is transiently activated after gamma-irradiation, it is eventually submitted to sustained down-regulation, presumably to allow development of MSL1-associated DNA-repair activity. We conclude that interaction of MSL1 with 53BP1 brings MSL1-dependent HAT activity to the vicinity of damaged DNA. MSL1-dependent HAT activity, which is negatively regulated by the stress protein p8, induces chromatin remodeling and relaxation allowing access to DNA of the repair machinery.

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Available from: Meritxell Gironella, Apr 10, 2014
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    • "Moreover, it can acetylate p53 in response to high levels of damage promoting p53-dependent transcription of pro-apoptotic genes [32]. Interestingly, hMSL1 is known to influence hMOF’s H4K16 acetylation activity [21], [33], and it has been shown to co-immunoprecipitate with the DNA repair mediator, 53BP1 [33]. "
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    ABSTRACT: hMSL2 (male-specific lethal 2, human) is a RING finger protein with ubiquitin ligase activity. Although it has been shown to target histone H2B at lysine 34 and p53 at lysine 351, suggesting roles in transcription regulation and apoptosis, its function in these and other processes remains poorly defined. To further characterize this protein, we have disrupted the Msl2 gene in chicken DT40 cells. Msl2(-/-) cells are viable, with minor growth defects. Biochemical analysis of the chromatin in these cells revealed aberrations in the levels of several histone modifications involved in DNA damage response pathways. DNA repair assays show that both Msl2(-/-) chicken cells and hMSL2-depleted human cells have defects in non-homologous end joining (NHEJ) repair. DNA damage assays also demonstrate that both Msl2 and hMSL2 proteins are modified and stabilized shortly after induction of DNA damage. Moreover, hMSL2 mediates modification, presumably ubiquitylation, of a key DNA repair mediator 53BP1 at lysine 1690. Similarly, hMSL1 and hMOF (males absent on the first) are modified in the presence of hMSL2 shortly after DNA damage. These data identify a novel role for Msl2/hMSL2 in the cellular response to DNA damage. The kinetics of its stabilization suggests a function early in the NHEJ repair pathway. Moreover, Msl2 plays a role in maintaining normal histone modification profiles, which may also contribute to the DNA damage response.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "There is also evidence that shows NUPR1 regulates autophagy and apoptosis and may be relevant to cardiovascular pathologies and cancers that associated with dysregulated autophagy (Kong et al., 2010). Recently, NUPR1 was found to regulate DNA-repair activity (Gironella et al., 2009) and represent a new node in a chromatin regulatory network (Sambasivan et al., 2009). Based on the previous reports, the stress protein NUPR1 plays a vital part in the metastasis, chemoresistance, survival or apoptosis of carcinoma, although this is not without controversy. "
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    ABSTRACT: NUPR1 (nuclear protein 1) was found to play a key role in the development of several malignancies including pancreas, breast, and prostate cancers. However, the functional role of NUPR1 in nonsmall cell lung cancer (NSCLC) progression and development is little known. Here, lentivirus-mediated small interfering RNA (siRNA) was employed to downregulate endogenous NUPR1 expression to study the function of NUPR1 in growth of nonsmall cell lung cancer. A lentivirus-mediated RNAi technology was used to specifically knock down the expression of NUPR1 in H1299 cells. Quantitative real-time reverse transcriptase polymerase chain reaction, flow cytometry, western blot and cell count assays were studied to characterize NUPR1 expression in vitro. Furthermore, nonsmall cell lung cancer xenograft models in nude mice were established to investigate whether knockdown of NUPR1 reduces the tumor growth in vivo. We found that downregulation of NUPR1 expression significantly inhibited nonsmall cell lung cancer H1299 cells proliferation and colony formation in vitro. Moreover, the specific downregulation of NUPR1 arrested cells in G0 phase of cell cycle and increased apoptosis rate. Silencing of NUPR1 also suppressed tumor growth by tail vein injection of lentivirus encoded shRNA against NUPR1 in vivo. Our findings revealed that the NUPR1 gene represents a promising target for gene silencing therapy in nonsmall cell lung cancer. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
    Preview · Article · Dec 2012 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
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    ABSTRACT: p8 (NUPR1 (nuclear protein-1), Com1 (candidate of metastasis-1)) is a protein related to the high mobility group of transcriptional regulators. It is a key player in the cellular stress response and is involved in metastasis. p8 was first identified as a gene induced in pancreatitis but has been since found overexpressed in several cancers and pathological conditions. Despite its small size and apparently simple structure, p8 functions in several biochemical and genetic pathways, and its expression is crucial for in vivo metastasis in mice, for cytokine induction of metalloproteases, and for stress-induced cardiomyocyte hypertrophy. Understanding p8 functions will provide new opportunities for developing more effective therapeutic approaches to cancer and cardiovascular diseases.
    Preview · Article · Nov 2009 · Journal of Biological Chemistry
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