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

Rizzardi, Lindsay F.; Coleman, Kate E.; Varma, Dileep; Matson, Jacob P.; Oh, Seeun; Cook, Jeanette Gowen

doi:10.1074/jbc.m114.614701

Cited by 33 publications

(43 citation statements)

References 80 publications

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“…Several other studies (Bendjennat et al 2003;Abbas et al 2008Abbas et al , 2010Nishitani et al 2008;Shibata et al 2011;Zhang et al 2013) explored CRL4 Cdt2 substrate degradation kinetics, and late p21 degradation is detectable in those studies but had not been investigated. We note also that these three proteins appear to reaccumulate at the end of S phase in reverse order relative to the order in which they are degraded (Nishitani et al 2008;Abbas et al 2010;Rizzardi et al 2014). Based on our observations, early Cdt1 degradation relative to p21 in S phase is likely due to differences in the efficiency with which different PIP degrons recruit Cdt2 (Fig.…”

Section: Discussionmentioning

confidence: 69%

“…We had previously used this strategy to analyze interactions of full-length Cdt1 with PCNA DNA and Cdt2 (Chandrasekaran et al 2011). As controls, we included a full-length GST-tagged p21 and a PIP mutant form of p21 that cannot bind PCNA, PIP m p21-GST (Rizzardi et al 2014). As expected, the PIP mutant p21, unlike the wild-type p21, did not bind PCNA DNA (Supplemental Fig.…”

Section: Differential Recruitment Of Pcna/cdt2 By Pip Degronsmentioning

confidence: 99%

“…The Cdt1 PIP degron confers an accelerated degradation rate Human Cdt1 codons 1-28 encode its single PIP degron, and, when fused to a heterologous substrate, this sequence is sufficient to confer CRL4 Cdt2 -mediated degradation (Senga et al 2006;Rizzardi et al 2014). Given our finding that Cdt1 is consistently the most rapidly degraded among the CRL4…”

Section: Crl4mentioning

confidence: 99%

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Sequential replication-coupled destruction at G1/S ensures genome stability

et al. 2015

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Timely ubiquitin-mediated protein degradation is fundamental to cell cycle control, but the precise degradation order at each cell cycle phase transition is still unclear. We investigated the degradation order among substrates of a single human E3 ubiquitin ligase, CRL4Cdt2 , which mediates the S-phase degradation of key cell cycle proteins, including Cdt1, PR-Set7, and p21. Our analysis of synchronized cells and asynchronously proliferating live single cells revealed a consistent order of replication-coupled destruction during both S-phase entry and DNA repair; Cdt1 is destroyed first, whereas p21 destruction is always substantially later than that of Cdt1. These differences are attributable to the CRL4 Cdt2 targeting motif known as the PIP degron, which binds DNA-loaded proliferating cell nuclear antigen (PCNA DNA ) and recruits CRL4 Cdt2 . Fusing Cdt1's PIP degron to p21 causes p21 to be destroyed nearly concurrently with Cdt1 rather than consecutively. This accelerated degradation conferred by the Cdt1 PIP degron is accompanied by more effective Cdt2 recruitment by Cdt1 even though p21 has higher affinity for PCNA DNA . Importantly, cells with artificially accelerated p21 degradation display evidence of stalled replication in mid-S phase and sensitivity to replication arrest. We therefore propose that sequential degradation ensures orderly S-phase progression to avoid replication stress and genome instability.

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Section: Discussionmentioning

confidence: 69%

Section: Differential Recruitment Of Pcna/cdt2 By Pip Degronsmentioning

confidence: 99%

Section: Crl4mentioning

confidence: 99%

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Sequential replication-coupled destruction at G1/S ensures genome stability

et al. 2015

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“…The first mechanism is mediated through the phosphorylation of CDT1 by the JNK and p38 kinases, thus preventing CDT1 recognition by the CRL4 CDT2 ligase [264]. In addition, a second mechanism ensures that CDT2 is prevented from being recruited to chromatin through its phosphorylation by CDK1 [265]. Notably, the re-accumulation of CDT1, similar to SET8, in G2 was shown to be important for cell cycle progression [265].…”

Section: F-box Proteins With Tumor-suppressive Propertiesmentioning

confidence: 99%

“…In addition, a second mechanism ensures that CDT2 is prevented from being recruited to chromatin through its phosphorylation by CDK1 [265]. Notably, the re-accumulation of CDT1, similar to SET8, in G2 was shown to be important for cell cycle progression [265]. Because extensive DNA re-replication is deleterious to cells, the re-replication resulting from failure to degrade CDT1 by FBXO31 in tumors with low or absent FBXO31 is likely to be only minor.…”

Section: F-box Proteins With Tumor-suppressive Propertiesmentioning

confidence: 99%

Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis

Heo

Eki

Abbas

2016

Seminars in Cancer Biology

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F-box proteins are substrate receptors of the SCF (SKP1-Cullin 1-F-box protein) E3 ubiquitin ligase that play important roles in a number of physiological processes and activities. Through their ability to assemble distinct E3 ubiquitin ligases and target key regulators of cellular activities for ubiquitylation and degradation, this versatile group of proteins is able to regulate the abundance of cellular proteins whose deregulated expression or activity contributes to disease. In this review, we describe the important roles of select F-box proteins in regulating cellular activities, the perturbation of which contributes to the initiation and progression of a number of human malignancies.

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Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death

et al. 2022

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Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+-ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin-receptor-/Akt-pathway-dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid-droplet-coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle-interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis-targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development.

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

Cited by 33 publications

References 80 publications

Sequential replication-coupled destruction at G1/S ensures genome stability

Sequential replication-coupled destruction at G1/S ensures genome stability

Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis

Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death

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