The NUCKS1-SKP2-p21/p27 axis controls S phase entry

Hume, Samuel; Grou, Cláudia P.; Lascaux, Pauline; D’Angiolella, Vincenzo; Legrand, Arnaud J.; Ramadan, Kristijan; Dianov, Grigory L.

doi:10.1038/s41467-021-27124-8

Cited by 36 publications

(30 citation statements)

References 80 publications

(109 reference statements)

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“…Nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1), involved in homologous recombination, is lost from chromatin upon etoposide treatment and at 24 hours release. This transcription factor binds chromatin in a cell cycle-dependent manner and its levels increase in late G1, thus explaining this enrichment on chromatin (Hume et al , 2021; Parplys et al , 2015). Similarly, structural maintenance of chromosome 4 (SMC4), a component of the condensin complex facilitating the sister-chromatid condensation and mitosis, which is also involved in DNA repair (Wang & Wu, 2021), is depleted from chromatin immediately after etoposide treatment, but unlike NUCKS1, it is fully restored to basal levels 24 hours after release.…”

Section: Resultsmentioning

confidence: 99%

A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

Moretton

Kourtis

Calabrò

et al. 2022

Preprint

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While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be reported. Here, we investigate the metabolic enzymes and processes that are essential when cells are exposed to DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 regulates aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of DNA damage, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.

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Section: Resultsmentioning

confidence: 99%

A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

Moretton

Kourtis

Calabrò

et al. 2022

Preprint

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“…Thus, we presume that p27 is a downstream factor of p53 and plays a role in suppressing anchorage-independent growth of cancer cells, which might be involved in promoting metastasis upon p53 inactivation. Recently, Hume et al, 2021. have reported that DNA damage induces p53-dependent transcriptional repression of NUCKS1, a positive regulator for a p27-targeting module SKP2 of the ubiquitin ligase SCF SKP2 , leading to an increase in p27 protein (Hume et al, 2021). This p53-dependent regulatory pathway for suppressing p27 degradation might also be involved in the anchorage-independent growth.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of p27Kip1 depending on culture conditions and its correlation with status of p14ARF and p53

Kometani¹,

Kawasaki²,

Chibazakura³

2022

Genes to Cells

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Cell cycle progression is strictly controlled by complexes of cyclins and cyclin-dependent kinases (CDKs). Disturbance of cell cycle regulation contributes to not only cell death but also carcinogenesis and cancer progression (Bartek & Lukas, 2007;Jackson & Bartek, 2009). p27 Kip1 is a major CDK inhibitor and inhibits CDK activity by binding to cyclin/CDK complex (Russo et al., 1996). p27 is regulated at expression level through transcriptional,

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“…6D). p53 is involved in regulating cycle-related proteins including P21 and P27 [26]. The nuclear accumulation of p53 could activate its functions [27].…”

Section: Xpo1 Inhibitor Kpt-330 Activated P53/mtor Pathway To Induce ...mentioning

confidence: 99%

Inhibition of XPO1 with KPT-330 induces autophagy-dependent apoptosis in gallbladder cancer by activating the p53/mTOR pathway

et al. 2022

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Background Gallbladder cancer (GBC) is a highly aggressive malignant cancer in the biliary system with poor prognosis. XPO1 (chromosome region maintenance 1 or CRM1) mediates the nuclear export of several proteins, mainly tumor suppressors. Thus, XPO1 functions as a pro-oncogenic factor. KPT-330 (Selinexor) is a United States Food and Drug Administration approved selective inhibitor of XPO1 that demonstrates good therapeutic effects in hematologic cancers. However, the function of XPO1 and the effect of KPT-330 have not been reported in GBC. Methods We analyzed the correlation between XPO1 expression levels by q-PCR and clinical features of GBC patients. Cell proliferation assays were used to analyze the in vitro antitumor effects of XPO1 inhibitor KPT-330. mRNA sequencing was used to explore the underlying mechanisms. Western blot was performed to explore the relationship between apoptosis and autophagy. The in vivo antitumor effect of KPT-330 was investigated in a nude mouse model of gallbladder cancer. Results We found that high expression of XPO1 was related to poor prognosis of GBC patients. We observed that XPO1 inhibitor KPT-330 inhibited the proliferation of GBC cells in vitro. Furthermore, XPO1 inhibitor KPT-330 induced apoptosis by reducing the mitochondrial membrane potential and triggering autophagy in NOZ and GBC-SD cells. Indeed, XPO1 inhibitor KPT-330 led to nuclear accumulation of p53 and activated the p53/mTOR pathway to regulate autophagy-dependent apoptosis. Importantly, KPT-330 suppressed tumor growth with no obvious toxic effects in vivo. Conclusion XPO1 may be a promising prognostic indicator for GBC, and KPT-330 appears to be a potential drug for treating GBC effectively and safely.

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The NUCKS1-SKP2-p21/p27 axis controls S phase entry

Cited by 36 publications

References 80 publications

A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

Differential regulation of p27Kip1 depending on culture conditions and its correlation with status of p14ARF and p53

Inhibition of XPO1 with KPT-330 induces autophagy-dependent apoptosis in gallbladder cancer by activating the p53/mTOR pathway

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