Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

Sideridou, Maria; Zakopoulou, Roubini; Evangelou, Konstantinos; Liontos, Michalis; Kotsinas, Athanassios; Rampakakis, Emmanouil; Gagos, Sarantis; Kahata, Kaoru; Grabušić, Kristina; Gkouskou, Kalliopi; Trougakos, Ioannis P.; Kolettas, Evangelos; Georgakilas, Alexandros G.; Volarević, Siniša; Eliopoulos, Aristides G.; Zannis‐Hadjopoulos, Maria; Moustakas, Aristidis; Gorgoulis, Vassilis G.

doi:10.1083/jcb.201108121

Cited by 90 publications

(111 citation statements)

References 59 publications

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“…It has been established that Cdc6 regulates pre-replication complex assembly mainly by recruiting the Mcm2-7 helicase to DNA replication origins, licensing replication initiation (Donovan et al, 1997;Liang and Stillman, 1997;Yan et al, 1998). It is also worth mentioning that two studies have revealed that Cdc6 represses Ecadherin locus or INK4/ARF locus transcription by binding to the promoter of these genes, inspiring the notion that Cdc6 also functions in transcription (Gonzalez et al, 2006;Sideridou et al, 2011). In this work, we found that Cdc6 localizes in the nucleolus in cycling cells at the end of mitosis and early G1 phase.…”

Section: Discussionmentioning

confidence: 99%

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Huang

Wang

et al. 2016

Journal of Cell Science

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RNA-polymerase-I-dependent ribosomal DNA (rDNA) transcription is fundamental to rRNA processing, ribosome assembly and protein synthesis. However, how this process is initiated during the cell cycle is not fully understood. By performing a proteomic analysis of transcription factors that bind RNA polymerase I during rDNA transcription initiation, we identified that the DNA replication initiator Cdc6 interacts with RNA polymerase I and its co-factors, and promotes rDNA transcription in G1 phase in an ATPaseactivity-dependent manner. We further showed that Cdc6 is targeted to the nucleolus during late mitosis and G1 phase in a manner that is dependent on B23 (also known as nucleophosmin, NPM1), and preferentially binds to the rDNA promoter through its ATP-binding domain. Overexpression of Cdc6 increases rDNA transcription, whereas knockdown of Cdc6 results in a decreased association of both RNA polymerase I and the RNA polymerase I transcription factor RRN3 with rDNA, and a reduction of rDNA transcription. Furthermore, depletion of Cdc6 impairs the interaction between RRN3 and RNA polymerase I. Taken together, our data demonstrate that Cdc6 also serves as a regulator of rDNA transcription initiation, and indicate a mechanism by which initiation of rDNA transcription and DNA replication can be coordinated in cells.

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Section: Discussionmentioning

confidence: 99%

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Huang

Wang

et al. 2016

Journal of Cell Science

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“…46 The molecular mechanism(s) by which Cdc6 expression makes HF more refractory to anagen-activating signals are not known and will require further investigation. They could involve the role of CDC6 in licensing replication origins, 18 its capacity to repress transcription, [15][16][17] or a combination of both. Finally, we conclude that Cdc6 overexpression by itself is not sufficient to promote skin tumors, at least in C57BL/6 mice, but its proto-oncogenic potential is unveiled in cooperation with DMBA-induced mutations.…”

Section: Discussionmentioning

confidence: 99%

“…13 The oncogenic potential of Cdc6 had been inferred from its capacity to induce DNA replication in quiescent cells, in cooperation with cycE-CDK2 14 as well as its ability to repress the expression of Ink4/Arf [15][16] and E-cadherin. 17 Cdc6 is overexpressed in subsets of brain tumors, mantle cell lymphomas and non-small cell lung carcinomas (reviewed in ref. 18 ).…”

Section: Introductionmentioning

confidence: 99%

Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle

et al. 2015

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Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage. While Cdc6 overexpression did not promote skin tumors, it facilitated the formation of papillomas in cooperation with mutagenic agents such as DMBA. In addition, the elevated levels of CDC6 protein in the skin extended the resting stage of the hair growth cycle, leading to better fur preservation in older mice.

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“…23 The same effect of overexpressed Cdc6 was also observed in human cells. 24 This phenotype was reversed when Cdc6 expression was shut down. Notably, flow cytometric analysis in mouse (P1) and human (A549) cells overexpressing Cdc6, revealed a significant increase of cells expressing the CD24 low /CD44 high antigen phenotype (Fig.…”

Section: Cdc6mentioning

confidence: 94%

Cdc6: A multi-functional molecular switch with critical role in carcinogenesis

2012

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Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins

Abstract: The Cdc6 replication licensing factor acts as a molecular switch at the E-cadherin locus, leading to E-cadherin transcriptional repression and local activation of replication.

Cited by 90 publications

References 59 publications

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation

Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle

Cdc6: A multi-functional molecular switch with critical role in carcinogenesis

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