Identification of cell cycle–regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors

Grant, Gavin D.; Brooks, Lionel; Zhang, Xiaoyang; Mahoney, James; Martyanov, Viktor; Wood, Tammara A.; Sherlock, Gavin; Cheng, Chao; Whitfield, Michael L.

doi:10.1091/mbc.e13-05-0264

Cited by 163 publications

(222 citation statements)

References 89 publications

(100 reference statements)

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“…2D), suggesting that another level of promoter regulation may exist, perhaps via binding to the adjacent CDE motif, which may be functional despite its imperfect match to the consensus. Considering that FOXM1 binds upstream of both the HJURP and CENP-A promoters and is itself repressed by p53 (Wang et al 2005(Wang et al , 2013Grant et al 2013;Zhang et al 2014;Yau et al 2015), it is tempting to speculate that FOXM1 could also contribute to a positive feedback loop of gene activation upon p53 loss. Interestingly, loss of FOXM1 is associated with phenotypes reminiscent of CENP-A loss, such as mitotic catastrophe (Wonsey and Follettie 2005).…”

Section: Discussionmentioning

confidence: 99%

Essential role for centromeric factors following p53 loss and oncogenic transformation

et al. 2017

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In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within the Hjurp and Cenpa promoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre-established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an "epigenetic addiction" to the HJURP chaperone represents an Achilles' heel in p53-deficient transformed cells.

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Section: Discussionmentioning

confidence: 99%

Essential role for centromeric factors following p53 loss and oncogenic transformation

et al. 2017

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“…HCT116 and HeLa cells were synchronized in early S phase by double thymidine block (2 mM thymidine for 17 h, release into fresh medium for 9 h, 2 mM thymidine for 15 h) or in prometaphase by treatment with 2 mM thymidine for 18 h followed by release into 100 nM nocodazole for 10 h as described previously (28,29). Kinase inhibitors were used at the following concentrations: c-Jun N-terminal kinase (JNK) inhibitor VIII at 10 M (EMD Millipore), p38 inhibitor SB203580 at 30 M (LC Laboratories), and the CDK1 inhibitor RO-3306 (Sigma) at 10 M or as indicated.…”

Section: Methodsmentioning

confidence: 99%

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

Rizzardi¹,

Coleman²,

Varma

et al. 2015

Journal of Biological Chemistry

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Background: CRL4CDT2 mediates replication-coupled destruction during S phase. CRL4 CDT2 substrates reaccumulate by an unexplored mechanism. Results: CDK1 activity blocks CRL4CDT2 by preventing chromatin recruitment of the substrate receptor, CDT2. Conclusion: CDK1 activity facilitates CRL4 CDT2 substrate reaccumulation upon S phase exit; several of these substrates are then required for normal mitotic progression. Significance: We provide the first evidence that CDK1 regulates the activity of CRL4 CDT2 .

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“…Previous studies in yeast, mouse and human cells have uncovered a periodic transcriptome comprised of classes of messenger RNAs (mRNAs) that oscillate during cell cycle and regulate cell cycle progression [2][3][4][5][6][7]. In addition to mRNAs, several RNAs of other types were also found to be periodic, including long non-coding RNAs (lncRNAs) [8,9] and short non-coding RNAs [8].…”

Section: Introductionmentioning

confidence: 99%

“…However, the prevalence of these periodic non-coding RNAs remains mostly unknown, as previous studies surveyed cell cycle-dependent transcriptomes using microarrays that are unable to detect these non-canonical RNA species. Furthermore, cell type-specific periodic transcripts have been observed across different cell types and related species [2,4], suggesting distinct regulatory mechanisms are in place to control periodicity in different cellular contexts. However, the commonly periodic (or cell type-independent) transcriptome is poorly defined, and the mechanisms that account for cell type differences remain unclear.…”

Section: Introductionmentioning

confidence: 99%

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

et al. 2016

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Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transcriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles (>2.3 billion paired reads), we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed "mitotic trait" that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing >4 000 tumor samples in The Cancer Genome Atlas (TCGA) and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes.

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Identification of cell cycle–regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors

Cited by 163 publications

References 89 publications

Essential role for centromeric factors following p53 loss and oncogenic transformation

Essential role for centromeric factors following p53 loss and oncogenic transformation

CDK1-dependent Inhibition of the E3 Ubiquitin Ligase CRL4CDT2 Ensures Robust Transition from S Phase to Mitosis

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

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