c-Myc Suppression of DNA Double-strand Break Repair

Li, Zhaozhong; Owonikoko, Taofeek K.; Sun, Shi-Yong; Ramalingam, Suresh S.; Doetsch, Paul W.; Xiao, Zhi‐Qiang; Khuri, Fadlo R.; Curran, Walter J.; Deng, Xingming

doi:10.1593/neo.121258

Cited by 53 publications

(50 citation statements)

References 55 publications

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“…In mammalian cells, overexpression of c-Myc increases the number of DNA double strand breaks (DSBs), as assayed by the level of γ-H2A.X, a phospho-histone marker of DSBs [9], [11]–[13], [15]. To determine if this is a conserved feature of Myc family proteins, we overexpressed Drosophila Myc in the dorsal compartment of the larval wing imaginal disc using apterous-Gal4 (ap-Gal4) and showed that this led to a ∼2-fold increase in the number of γ-H2A.X positive cells (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

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Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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The Myc family of transcription factors are key regulators of cell growth and proliferation that are dysregulated in a large number of human cancers. When overexpressed, Myc family proteins also cause genomic instability, a hallmark of both transformed and aging cells. Using an in vivo lacZ mutation reporter, we show that overexpression of Myc in Drosophila increases the frequency of large genome rearrangements associated with erroneous repair of DNA double-strand breaks (DSBs). In addition, we find that overexpression of Myc shortens adult lifespan and, conversely, that Myc haploinsufficiency reduces mutation load and extends lifespan. Our data provide the first evidence that Myc may act as a pro-aging factor, possibly through its ability to greatly increase genome instability.

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Section: Resultsmentioning

confidence: 99%

“…Overexpression of Myc family proteins increases genomic instability [6], [9], [12], [24]–[26], [47]. While understanding the effects of overexpressed Myc has clear relevance for understanding diseases caused by dysregulation of Myc such as cancer, we also wish to test a role for endogenous Myc in influencing mutation load.…”

Section: Resultsmentioning

confidence: 99%

Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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“…3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. [12][13][14][15] The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains. 16,17 Ku70 usually heterodimerizes with Ku86, which forms a functional complex for DSB repair.…”

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confidence: 99%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

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Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) Mcl-1 is an antiapoptotic molecule that is overexpressed in various types of cancers, including lung cancer, 1 leukemia, 2 lymphoma, 3 hepatocellular carcinoma 4 and so on. In addition to its antiapoptotic function, Mcl-1 is also an oncoprotein that promotes the development of cancer. 5 In contrast to other Bcl2 family members such as Bcl2 and Bcl-XL, Mcl-1 is unique in its short half-life (30 min-3 h) and short-term prosurvival function, which probably relates to the presence of a long proline-, glutamic acid-, serine-and threonine-rich (PEST) region upstream of the Bcl2 homology (BH) domain. 1 The mechanism(s) that stabilizes the Mcl-1 protein are critical for its long-term survival function. Mcl-1 protein can be phosphorylated at multiple sites that distinctly regulate Mcl-1 protein turnover. For example, extracellular signal-regulated kinase 1/2-mediated T163 site phosphorylation enhances the half-life and antiapoptotic function of Mcl-1. 1,6 In contrast, S159 phosphorylation by GSK-3b facilitates Mcl-1 ubiquitination and degradation to reduce its survival activity. 7 Ubiquitination and deubiquitination are two reversible processes that can control protein stability. E3 ligases and deubiquitinases (deubiquitinating enzymes (DUBs)) are two groups of regulatory enzymes that orchestrate the ubiquitination levels of target proteins in eukaryotic cells. 8 Recently, Mule and FBW7 have been identified as Mcl-1 ubiquitin E3 ligases that can directly induce polyubiquitination and degradation of Mcl-1. 9,10 Inversely, USP9X has been demonstrated as the Mcl-1 deubiquitinase that removes the Lys 48-linked polyubiquitin chains that normally mark Mcl-1 for proteasomal degradation, leading to stabilization of Mcl-1. 3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. 12-15 The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains. 16,17 Ku70 usually heterodimerizes with Ku86, which forms a functional complex for DSB repair. By forming a bridge between the broken DNA ends, the Ku70/Ku86 heterodimer acts to structurally support and align the DNA ends, to protect them from degradation and to prevent promiscuous binding to unbroken DNA. Ku70/Ku86 effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. 18 In some cases, a fourth domain is present at the C terminus of Ku86, which binds to the DNA-dependent protein kinase catalytic subunit...

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“…In addition to DNA-PKcs and c-Mycmediated functional regulation [31,32], it is interesting to answer whether DNA-PK can act as a platform when interacting with c-Myc to mediate its direct involvement on DNA damage response. After a DSB, histone H2AX is phosphorylated at Ser139 to form c-H2AX foci enriched at DSB sites to function as a molecular machine of DNA damage signalling and response [33].…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies regarding the involvement of c-Myc in regulating cellular sensitivity to ionizing radiation, major attentions have been paid to c-Myc-mediated regulation of apoptosis or of repair genes expression or to the regulation of autophagy or the ageing process [26,31,32,37]. In recent years, studies on the various checkpoints in the c-Myc-mediated regulation of energy metabolism or carcinogenesis have provided new hypotheses regarding the consideration of c-Myc as a molecular target in cancer therapy [38,39].…”

Section: Discussionmentioning

confidence: 99%

The involvement of c-Myc in the DNA double-strand break repair via regulating radiation-induced phosphorylation of ATM and DNA-PKcs activity

et al. 2015

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Deregulation of c-Myc often occurs in various human cancers, which not only contributes to the genesis and progression of cancers but also affects the outcomes of cancer radio- or chemotherapy. In this study, we have investigated the function of c-Myc in the repair of DNA double-strand break (DSB) induced by γ-ray irradiation. A c-Myc-silenced Hela-630 cell line was generated from HeLa cells using RNA interference technology. The DNA DSBs were detected by γ-H2AX foci, neutral comet assay and pulsed-field gel electrophoresis. We found that the capability of DNA DSB repair in Hela-630 cells was significantly reduced, and the repair kinetics of DSB was delayed as compared to the control Hela-NC cells. Silence of c-myc sensitized the cellular sensitivity to ionizing radiation. The phosphorylated c-Myc (Thr58/pSer62) formed the consistent co-localisation foci with γ-H2AX as well as the phosphorylated DNA-PKcs/S2056 in the irradiated cells. Moreover, depression of c-Myc largely attenuated the ionizing radiation-induced phosphorylation of the ataxia telangiectasia mutated (ATM) and decreased the in vitro kinase activity of DNA-PKcs. Taken together, our results demonstrated that c-Myc protein functions in the process of DNA double-strand break repair, at least partially, through affecting the ATM phosphorylation and DNA-PKcs kinase activity. The overexpression of c-Myc in tumours can account for the radioresistance of some tumour cell types.

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c-Myc Suppression of DNA Double-strand Break Repair

Cited by 53 publications

References 55 publications

Myc-Dependent Genome Instability and Lifespan in Drosophila

Myc-Dependent Genome Instability and Lifespan in Drosophila

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

The involvement of c-Myc in the DNA double-strand break repair via regulating radiation-induced phosphorylation of ATM and DNA-PKcs activity

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