Inactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer

Ghamrasni, Samah El; Pamidi, Ashwin; Halaby, Marie Jo; Bohgaki, Miyuki; Cardoso, Renato; Li, Li; Somasundaram, Venkatesan; Sethu, Swaminathan; Hirao, Atsushi; Mak, Tak W.; Hande, M. Prakash; Hakem, Anne; Hakem, Razqallah

doi:10.1371/journal.pgen.1001385

Cited by 18 publications

(9 citation statements)

References 33 publications

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“…Interestingly, our results also showed that CHK2 inhibitor could slightly aggravating Mus81 deficiency-induced S-phase arrest and apoptosis in response to EPI. These data was consistent with the results from a recent study, which showing that dual inactivation of CHK2 and Mus81 leads to cell death of lymphoid cells despite the underlying mechanism remaining unknown [34]. Our western blot results subsequently indicated that the activity of CHK1 pathway was slightly elevated in Mus81-inhibited HepG2 cells after CHK2 inhibition, thereby promoting the activity of p53, Bax, and Caspase-3, which might be the mechanisms underlying the deteriorative S-phase arrest and apoptosis induced by CHK2 inhibition in Mus81 depleted HCC cells.…”

Section: Discussionsupporting

confidence: 93%

Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway

Chen

Yan

et al. 2015

Cancer Medicine

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As a critical endonuclease in DNA repair, Mus81 is traditionally regarded as a tumor suppressor, but recently correlated with the sensitivity of mitomycin C and 5‐fluorouracil in colon cancer and breast cancer cells. However, its role in chemosensitivity of other human malignancies still remains unknown. This study therefore aims to investigate the effects of Mus81 knockdown on the chemosensitivity of hepatocellular carcinoma (HCC), a usually chemorefractory tumor, and explore the underlying mechanisms. Mus81 expression in HepG2 and Bel‐7402 HCC cell lines was depleted by lentivirus‐mediated short hairpin RNA and the elevated sensitivity of these Mus81‐inhibited HCC cells to therapeutic agents, especially to epirubicin (EPI), was evidenced by MTT assay and an HCC chemotherapy mouse model. Flow cytometric analysis also showed that Mus81 knockdown lead to an obvious S‐phase arrest and an elevated apoptosis in EPI‐treated HepG2 and Bel‐7402 cells, which could be rescued by CHK1 inhibition. The activation of CHK1/CDC25A/CDK2 pathway was also demonstrated in Mus81‐inhibited HepG2 cells and xenograft mouse tumors under EPI treatment. Meanwhile, the apoptosis of HepG2 cells in response to EPI was remarkably promoted by Mus81 knockdown through activating p53/Bax/Caspase‐3 pathway under the controlling of CHK1. In addition, CHK2 inhibition slightly raised CHK1 activity, thereby enhancing the S‐phase arrest and apoptosis induced by EPI in Mus81‐suppressed HCC cells. In conclusion, Mus81 knockdown improves the chemosensitivity of HCC cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway, suggesting Mus81 as a novel therapeutic target for HCC.

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Section: Discussionsupporting

confidence: 93%

Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway

Chen

Yan

et al. 2015

Cancer Medicine

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“…Broadly defined as ‘checkpoint abrogation’, this strategy relies on the premise that pharmacologic inhibition of Chk2 (and Chk1) may prevent cell cycle arrest in response to DNA damage, and thus sensitize tumor cells to apoptosis (44). While validating Chk2 as an important cancer therapeutic target (45), the data presented also anticipate a broader role of this pathway in tumor progression, via exploitation of the survivin network. Mechanistically, this may involve Chk2-mediated release of cytoprotective survivin from its mitochondrial stores during DNA damage (18), coupled with efficient DSB sensing via phosphorylation of survivin-ΔEx3 (this study).…”

Section: Discussionmentioning

confidence: 73%

Chk2 Phosphorylation of Survivin-ΔEx3 Contributes to a DNA Damage–Sensing Checkpoint in Cancer

et al. 2012

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Survivin is an oncogene that functions in cancer cell cytoprotection and mitosis. Here we report that differential expression in cancer cells of a C-terminal splice variant of survivin, termed survivin-ΔEx3, is tightly associated with aggressive disease and markers of unfavorable prognosis. In contrast to other survivin variants, survivin-ΔEx3 localized exclusively to nuclei in tumor cells and was phosphorylated at multiple residues by the checkpoint kinase Chk2 during DNA damage. Mutagenesis of the Chk2 phosphorylation sites enhanced the stability of survivin-ΔEx3 in tumor cells, inhibited the expression of phosphorylated H2AX (γH2AX) in response to double strand DNA breaks, and impaired growth after DNA damage. DNA damage-induced Chk2 phosphorylation, stabilization of p53, induction of the cyclin-dependent kinase inhibitor p21, and homologous recombination-induced repair were not affected. In vivo, active Chk2 was detected at the earliest stages of the colorectal adenoma-to-carcinoma transition, persisted in advanced tumors, and correlated with increased survivin expression. Together, our findings suggest that Chk2-mediated phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint that may affect cancer cell sensitivity to genotoxic therapies.

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“…Accordingly, decreased levels of MUS81 expression have been found in hepatic metastasis and correlated with poor cancer prognosis [43] (Table 2 ). A role for MUS81 in tumorigenesis is further supported by evidence of a synergistic effect with inactivation of p53 and, on the other hand, suppression by inactivating CHK2 [44]. This all together suggests MUS81 to be a potential target for cancer therapy.…”

Section: Introductionmentioning

confidence: 81%

Nucleases in homologous recombination as targets for cancer therapy

Bartošová

Krejčí

2014

FEBS Letters

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a b s t r a c tGenomic DNA is constantly challenged from endogenous as well as exogenous sources. The DNA damage response (DDR) mechanism has evolved to combat these challenges and ensure genomic integrity. In this review, we will focus on repair of DNA double-strand breaks (DSB) by homologous recombination and the role of several nucleases and other recombination factors as suitable targets for cancer therapy. Their inactivation as well as overexpression have been shown to sensitize cancer cells by increasing toxicity to DNA-damaging agents and radiation or to be responsible for resistance of cancer cells. These factors can also be used in targeted cancer therapy by taking advantage of specific genetic abnormalities of cancer cells that are not present in normal cells and that result in cancer cell lethality.

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Inactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer

Cited by 18 publications

References 33 publications

Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway

Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway

Chk2 Phosphorylation of Survivin-ΔEx3 Contributes to a DNA Damage–Sensing Checkpoint in Cancer

Nucleases in homologous recombination as targets for cancer therapy

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