Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication

Zeng, Jingkun; Hills, Stephanie A.; Ozono, Eiko; Diffley, John F.X.

doi:10.1016/j.cell.2022.12.036

Cited by 55 publications

(47 citation statements)

References 42 publications

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“…Furthermore, analysis of the aneuploidy score indicated that lower levels of RNF144B mRNA correlated with chromosomal abnormalities in LUAD patients with wild-type TP53. This supports previous ndings suggesting that TP53 may not be fully essential for maintaining a correct ploidy, and whole-genome doubling can occur even in the presence of functional TP53 [56][57][58][59] . In most of the cases reported, poor checkpoint regulation due to overexpression of speci c cyclins or spindle assembly factors were the cause for the appearance of mitotic slippage and subsequent tetraploidization 56,57, 59-61 .…”

Section: Discussionsupporting

confidence: 91%

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Abad,

Sandoz,

Romero

et al. 2023

Preprint

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The tumor suppressor protein TP53 regulates a vast transcriptional program that serves protective mechanisms against cancer development. However, the complexity of this program makes it difficult to unravel the role of each of its targets in TP53-mediated tumour suppression. Knockdown of RNF144B, a E3-ubiquitin ligase transcriptionally regulated by TP53, enhanced the rate of tumour development and severity of malignant disease in the context of murine c-MYC-driven lymphomagenesis. Here we asked whether RNF144B has an impact on tumor suppression beyond the hematopoietic compartment. Integrative transcriptomics, proteomics, genomics and functional analysis of human and mouse oncogene-expressing cells with TP53 wild-type revealed a role for RNF144B in coordinating cellular proliferation and transformation, DNA repair and genome stability. Moreover, we show that in the context of lung adenocarcinomas, RNF144B deficiency leads to resistance to cytotoxic drugs that induce DNA damage and chromosomal instability, and that patients have a worse disease-survival overall. Supported by clinical data, our study suggests that RNF144B governs genomic stability during transformation suppression, which could explain its inactivation in human cancers.

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Section: Discussionsupporting

confidence: 91%

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Abad,

Sandoz,

Romero

et al. 2023

Preprint

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“…Levels of chromatin-bound Mcm2 increase during the G1 phase, peak at the G1/S transition, decrease during the S phase, and become lowest at the G2 phase (Mcm2, passage 18, Fig. 3B) (Zhou et al , 2020; Hayashi-Takanaka et al , 2021; Zeng et al , 2023). Immunostaining of passage 32 cells with an anti-Orc6 antibody occasionally showed enlarged nuclei with high levels of chromatin-bound Orc6 (arrows in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Low levels of proteasome activity are observed in replicative senescent cells (Sabath et al , 2020), and its inhibition induces cellular senescence in normal human fibroblasts (Chondrogianni et al , 2003; Chondrogianni & Gonos, 2004; Ukekawa et al , 2004; Torres et al , 2006). Senescent cells are produced by evading mitosis and exhibit chromatin-bound pre-RCs, indicating their presence in the tetraploid G1 phase (Panopoulos et al , 2014; Johmura et al , 2014; Zeng et al , 2023). However, the role of proteasome activity in pre-RC formation during cellular senescence remains elusive.…”

mentioning

confidence: 99%

Orc6 dissociation from chromatin prevents premature loading of MCM at G2 and tetraploid production

Hayashi-Takanaka,

Hiratani,

Haraguchi

et al. 2024

Preprint

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DNA replication is tightly regulated to occur only once per cell cycle. The untimely initiation of DNA replication can result in genome instability, leading to aneuploidy, which has been associated with early senescence and cancer. The pre-replication complex, comprising the origin recognition complex (ORC; Orc1-6), Cdc6, Cdt1, and MCM, is required for initiating DNA replication, although the function of Orc6 is yet to be elucidated. Here, we show that Orc6 dissociates from chromatin upon entering the S-phase and that the Orc6 dissociation depends on proteasome activity. Treatment that inhibits proteasome activity, which declines with aging, increases the senescence marker p21 levels, and promotes cell cycle arrest in human immortalized hTERT-RPE1 cells. This treatment induced large nuclei with high levels of chromatin-bound Orc6 and MCM without undergoing mitosis. When the proteasome activity recovered, those cells with high levels of chromatin-bound Orc6 and MCM proceeded to whole-genome DNA replication, confirming that they were tetraploid G1 cells. We propose that proteasome-dependent dissociation of Orc6 from chromatin after S-phase is essential for preventing MCM reloading and the subsequent development of tetraploid cells.

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“…One common type of chromosomal alteration is a whole-genome duplication (WGD) event, in which a cell's chromosome complement doubles. The causes and consequences of WGDs are poorly understood; mutations in TP53 have been linked with WGD development but other genetic and environmental causes remain obscure 43,47,48 . WGDs enhance tumor adaptability and increase metastatic dissemination, potentially by enhancing tumor heterogeneity and allowing cancers to sample a wider range of karyotypes 47,[49][50][51] .…”

Section: Introductionmentioning

confidence: 99%

An elevated rate of whole-genome duplications associated with carcinogen exposure in Black cancer patients

Brown,

Hagenson,

Koklič

et al. 2023

Preprint

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In the United States, Black individuals have higher rates of cancer mortality than any other racial or ethnic group. The sources of these significant racial disparities are not fully understood, and may include social, environmental, and genetic factors that influence cancer onset, diagnosis, and treatment. Here, we examined genomic data from several large-scale cancer patient cohorts to search for racial associations in chromosome copy number alterations. We found that tumors from Black patients were significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from white patients. Among patients with WGD-positive cancers, there was no significant difference in survival between Black and white patients, suggesting that the increased incidence of WGD events could contribute to the disparities in patient outcome. Genomic analysis identified several somatic alterations associated with WGD events that were consistent between Black and white populations, indicating that the increase in WGD events may be driven by environmental or epigenetic factors in Black patients. In total, these findings identify a class of genomic alterations that may influence racial disparities in cancer patient outcome. As cancers that have undergone WGD events exhibit unique genetic vulnerabilities, therapies that selectively target WGD-positive cancers may be particularly effective at treating aggressive malignancies in Black patients.

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Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication

Cited by 55 publications

References 42 publications

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Orc6 dissociation from chromatin prevents premature loading of MCM at G2 and tetraploid production

An elevated rate of whole-genome duplications associated with carcinogen exposure in Black cancer patients

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