Human SMC2 Protein, a Core Subunit of Human Condensin Complex, Is a Novel Transcriptional Target of the WNT Signaling Pathway and a New Therapeutic Target

Dávalos, Verónica; Suárez-López, Lucía; Castaño, Julio; Messent, Anthea J.; Abasolo, Ibane; Fernández, Yolanda; Guerra-Moreno, Ángel; Espín, Eloy; Armengol, Manel; Musulén, Eva; Ariza, Aurelio; Sayós, Joan; Arango, Diego

doi:10.1074/jbc.m112.428466

Cited by 49 publications

(63 citation statements)

References 34 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

View full text Add to dashboard Cite

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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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“…In this study, we found that SMC2 interacts with MYCN and is involved in transcriptional regulation of DDR genes, and that SMC2 expression is regulated by MYCN as well as by Wnt 54 (Fig. 6C).…”

Section: Discussionmentioning

confidence: 51%

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

et al. 2014

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The condensin complex is required for chromosome condensation during mitosis; however, the role of this complex during interphase is unclear. Neuroblastoma is the most common extracranial solid tumor of childhood, and it is often lethal. In human neuroblastoma, MYCN gene amplification is correlated with poor prognosis. This study demonstrates that the gene encoding the condensin complex subunit SMC2 is transcriptionally regulated by MYCN. SMC2 also transcriptionally regulates DNA damage response genes in cooperation with MYCN. Downregulation of SMC2 induced DNA damage and showed a synergistic lethal response in MYCN-amplified/overexpression cells, leading to apoptosis in human neuroblastoma cells. Finally, this study found that patients bearing MYCN-amplified tumors showed improved survival when SMC2 expression was low. These results identify novel functions of SMC2 in DNA damage response, and we propose that SMC2 (or the condensin complex) is a novel molecular target for the treatment of MYCN-amplified neuroblastoma.

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Human SMC2 Protein, a Core Subunit of Human Condensin Complex, Is a Novel Transcriptional Target of the WNT Signaling Pathway and a New Therapeutic Target

Cited by 49 publications

References 34 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

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

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

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