Cell cycle inertia underlies a bifurcation in cell fates after DNA damage

Nathans, Jenny F.; Cornwell, James; Afifi, Marwa M.; Paul, Debasish; Cappell, Steven D.

doi:10.1126/sciadv.abe3882

Cited by 28 publications

(27 citation statements)

References 42 publications

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“…This corresponds with early reports of restriction point timing (Campisi et al, 1982;Foster et al, 2010;Yen & Pardee, 1978). This could reflect an increasing rate of p21 degradation as cells approach the G1/S transition (Heldt et al, 2018;Nathans et al, 2021) or could be the result of a change in the dependency of cells on CDK4/6 activity for cell cycle progression at the restriction point. Since we see no change in sensitivity of G1 cells to Palbociclib in the absence of p21 and/or p27, it is likely that it is the latter hypothesis that is correct here and that cells only require CDK4/6 activity in early and mid G1 to complete the cell cycle.…”

Section: Discussionsupporting

confidence: 88%

“…In this case, whilst CDK4/6 may be inhibited by Palbociclib during the whole cell cycle, this does not affect progression until G1. Alternatively, this could be explained by the indirect model (Figure 1a) as p21 is degraded abruptly at S-phase entry (Barr et al, 2017;Bornstein et al, 2003;Heldt et al, 2018;Nathans et al, 2021) and is therefore only present at high levels during G1 (Rubin et al 2020).…”

Section: P21 and P27 Are Not Required For Entry Into G1 Arrest With Palbociclib In Rpe1 Cellsmentioning

confidence: 99%

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Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook

Barr

2021

Preprint

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The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data has cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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Section: Discussionsupporting

confidence: 88%

Section: P21 and P27 Are Not Required For Entry Into G1 Arrest With Palbociclib In Rpe1 Cellsmentioning

confidence: 99%

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook

Barr

2021

Preprint

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“…This corresponds with early reports of restriction point timing [ 60 – 62 ]. This could reflect an increasing rate of p21 degradation as cells approach the G1/S transition [ 50 , 51 ] or could be the result of a change in the dependency of cells on CDK4/6 activity for cell cycle progression at the restriction point. Since we see no change in sensitivity of G1 cells to palbociclib in the absence of p21 and/or p27, it is likely that it is the latter hypothesis that is correct here and that cells only require CDK4/6 activity in early and mid G1 to complete the cell cycle [ 15 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook

Barr

2021

Open Biol.

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The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data have cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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“…CDK2 encodes a form of protein-dependent kinases ( Nathans et al, 2021 ), involved in cell cycle regulation, with a critical role during the G1 to S phase transition. Decreased CDK2 expression can block cell cycle progression and inhibit the proliferation of pulmonary artery smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses

et al. 2021

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ObjectiveThe aim of this study is the identification of hub genes associated with idiopathic pulmonary arterial hypertension (IPAH).Materials and MethodsGSE15197 gene expression data was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by screening IPAH patients and controls. The 5,000 genes with the greatest variances were analyzed using a weighted gene co-expression network analysis (WGCNA). Modules with the strongest correlation with IPAH were chosen, followed by a functional enrichment analysis. Protein–protein interaction (PPI) networks were constructed to identify hub gene candidates using calculated degrees. Real hub genes were found from the overlap of DEGs and candidate hub genes. microRNAs (miRNAs) targeting real hub genes were found by screening miRNet 2.0. The most important IPAH miRNAs were identified.ResultsThere were 4,395 DEGs identified. WGCNA indicated that green and brown modules associated most strongly with IPAH. Functional enrichment analysis showed that green and brown module genes were mainly involved in protein digestion and absorption and proteoglycans in cancer, respectively. The top ten candidate hub genes in green and brown modules were identified, respectively. After overlapping with DEGs, 11 real hub genes were identified: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1. These genes were expressed with significant differences in IPAH versus controls, indicating a high diagnostic ability. The miRNA–gene network showed that hsa-mir-1-3p could associate with IPAH.ConclusionEP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1 may play essential roles in IPAH. Predicted miRNA hsa-mir-1-3p could regulate gene expression in IPAH. Such hub genes may contribute to the pathology and progression in IPAH, providing potential diagnostic and therapeutic opportunities for IPAH patients.

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Cell cycle inertia underlies a bifurcation in cell fates after DNA damage

Cited by 28 publications

References 42 publications

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses

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