Inactivation of SMC2 shows a synergistic lethal response in<i>MYCN</i>-amplified neuroblastoma cells

Murakami-Tonami, Yuko; Kishida, Satoshi; Takeuchi, Ichiro; Katou, Yuki; Maris, John M.; Ichikawa, Hitoshi; Kondo, Yutaka; Sekido, Yoshitaka; Shirahige, Katsuhiko; Murakami, Hiroshi; Kadomatsu, Kenji

doi:10.4161/cc.27983

Cited by 37 publications

(41 citation statements)

References 59 publications

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“…The structural maintenance of chromosomes protein-2 encoded by SMC2 is a core component of the condensin complex that is responsible for close packaging of chromatin before cell division (55). Moreover, SMC2 is a direct transcriptional target of oncogenic WNT signaling and N-Myc (56,57), and is emerging as a critical player in the DNA damage response (58). The index risk SNP at one of the seven new cross-cancer susceptibility loci discussed here was a genotyped SNP while at four other loci we were able to identify a genotyped SNP in the same region that was also genome-wide significant at P < 10 −8 .…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Kar¹,

Beesley²,

Olama³

et al. 2016

Cancer Discovery

175

148

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Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identifi ed at P < 10 −8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11 ; rs7937840/11q12/ INCENP ; rs1469713/19p13/ GATAD2A ), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2 ; rs8037137/15q26/ RCCD1 ), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4 ; rs9375701/6q23/ L3MBTL3 ). Index variants in fi ve additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specifi c expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed signifi cant enrichment of death receptor signaling genes near loci with P < 10 −5 in the three-cancer meta-analysis. SIGNIFICANCE:We demonstrate that combining large-scale GWA meta-analysis fi ndings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identifi cation of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Kar¹,

Beesley²,

Olama³

et al. 2016

Cancer Discovery

175

148

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“…Indeed, mutations or altered expression of condensin subunits are associated with several cancer types (Emmanuel et al, 2011; Leiserson et al, 2014; Murakami-Tonami et al, 2014; Ryu et al, 2007); HECTD1 expression is elevated in ER-α-positive breast cancer patients in Oncomine databases (Figure S7I), and is important for ER-α-negative breast cancer cell invasion and metastasis (Li et al, 2013b). Given the important roles of condensins acting on tightly regulated specific genomic regions (e.g.…”

Section: Discussionmentioning

confidence: 99%

Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation

et al. 2015

Molecular Cell

101

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Summary Enhancers instruct spatio-temporally specific gene expression in a manner tightly linked to higher-order chromatin architecture. Critical chromatin architectural regulators condensin I and condensin II play non-redundant roles controlling mitotic chromosomes. But aspects of interphase condensin loading and function, or in transcription regulation remain unclear. Here we report that both condensin complexes exhibit an unexpected, dramatic estrogen-induced recruitment to estrogen receptor α (ER-α)-bound eRNA+ active enhancers in interphase breast cancer cells, exhibiting non-canonical interaction with ER-α via its DNA-binding domain (DBD). Condensins positively regulate ligand-dependent enhancer activation, at least in part, by recruiting an E3 ubiquitin ligase, HECTD1, to modulate the binding of enhancer-associated coactivators/corepressors, including p300 and RIP140, permitting full eRNA transcription, formation of enhancer:promoter looping and the resultant coding gene activation. Collectively, our results reveal an important, unanticipated transcriptional role of interphase condensins in modulating estrogen-regulated enhancer activation and coding gene transcriptional program.

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“…Cohesin mutations have been identified in myeloid leukemias (Leeke et al, 2014). The condensin component Smc2 and the Smc5/6 complex component Smc6 are overexpressed in cancers, such as colorectal, neuroblastoma and breast cancer (Davalos et al, 2012;Murakami-Tonami et al, 2014;Stevens et al, 2011). Furthermore, mutation of Smc5 is linked to the development of brain metastases (Saunus et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

Pryzhkova¹,

Jordan²

2016

Development

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Correct duplication of stem cell genetic material and its appropriate segregation into daughter cells are requisites for tissue, organ and organism homeostasis. Disruption of stem cell genomic integrity can lead to developmental abnormalities and cancer. Roles of the Smc5/6 structural maintenance of chromosomes complex in pluripotent stem cell genome maintenance have not been investigated, despite its important roles in DNA synthesis, DNA repair and chromosome segregation as evaluated in other model systems. Using mouse embryonic stem cells (mESCs) with a conditional knockout allele of Smc5, we showed that Smc5 protein depletion resulted in destabilization of the Smc5/6 complex, accumulation of cells in G2 phase of the cell cycle and apoptosis. Detailed assessment of mitotic mESCs revealed abnormal condensin distribution and perturbed chromosome segregation, accompanied by irregular spindle morphology, lagging chromosomes and DNA bridges. Mutation of Smc5 resulted in retention of Aurora B kinase and enrichment of condensin on chromosome arms. Furthermore, we observed reduced levels of Polo-like kinase 1 at kinetochores during mitosis. Our study reveals crucial requirements of the Smc5/6 complex during cell cycle progression and for stem cell genome maintenance.

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Inactivation of SMC2 shows a synergistic lethal response inMYCN-amplified neuroblastoma cells

Cited by 37 publications

References 59 publications

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

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