A Novel Function of CRL4Cdt2

Zhang, Sufang; Zhao, Hong; Darzynkiewicz, Zbigniew; Zhou, Pengbo; Zhang, Zhongtao; Lee, Ernest Y.C.; Lee, Marietta Y.W.T.

doi:10.1074/jbc.m113.490466

Cited by 47 publications

(48 citation statements)

References 81 publications

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“…CDT2 is the substrate receptor of the CRL4 CDT2 ubiquitin ligase complex, which targets for destruction a number of substrates, among which the licensing factor CDT1 [2, 3, 5, 6], the CDK inhibitor p21 [7, 8], the checkpoint kinase CHK1 [13] and the p12 subunit of the DNA polymerase δ [20, 21]. CDT1 is a component of the prereplication complex that should be disassembled once the DNA synthesis begins.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, SET8 destruction promotes also transcription and prevents premature chromatin compaction [9, 16]. Moreover, the CRL4 CDT2 targets the controller of heterochromatin assembly Epe1 [17], the transcription factor E2F in flies [18], the DNA polymerase η in worms [19] and the p12 subunit of the DNA polymerase δ in humans [20, 21], and in fission yeast the ribonucleotide reductase inhibitor Spd1 [22]. …”

Section: Introductionmentioning

confidence: 99%

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The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

et al. 2014

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CDT2/L2DTL/RAMP is one of the substrate receptors of the Cullin Ring Ubiquitin Ligase 4 that targets for ubiquitin mediated degradation a number of substrates, such as CDT1, p21 and CHK1, involved in the regulation of cell cycle and survival. Here we show that CDT2 depletion was alone able to induce the apoptotic death in 12/12 human cancer cell lines from different tissues, regardless of the mutation profile and CDT2 expression level. Cell death was associated to rereplication and to loss of CDT1 degradation. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to a single specific pathway. CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

et al. 2014

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“…UV-mediated CRL4A activation induces ubiquitination of other key regulators of DNA replication such as the replication licensing factors Cdt1 and Mcm10 as well as the p12 subunit of the DNA replication polymerase δ (Higa et al, 2003; Hu et al, 2004; Kaur et al, 2012; Zhang et al, 2013; Zhong et al, 2003). Two groups have reported that CRL4s also promote the degradation of the essential tumor suppressing transcription factor p53, which controls the transcription of numerous DNA repair, checkpoint and apoptosis genes (Banks et al, 2006; Thirunavukarasou et al, 2014).…”

Section: Cellular and Developmental Functions Of Crl4 Ligasesmentioning

confidence: 99%

“…Zhang et al determined that DNA polymerase δ, which participates in DNA replication as well as repair, is also regulated by CRL4 ligases in a similar manner (Zhang et al, 2013). Building on work showing that the p12 subunit of the Pol δ heterotetramer contains a PIP box and is sharply downregulated after UV irradiation, they showed that knockdown of CUL4A and Cdt2 shields p12 from UV-induced degradation and that PIP box mutations stabilized p12 during S phase (Zhang et al, 2013).…”

Section: Cellular and Developmental Functions Of Crl4 Ligasesmentioning

confidence: 99%

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Hannah

Zhou

2015

Gene

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The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.

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“…In yeast, genetic evidence has shown clearly that polymerase δ is important for HR and gene conversion (Holmes and Haber, 1999; Maloisel et al, 2008) but these results have not yet been confirmed in human cells. Moreover, it has been recently shown that the subunit p12 of Polδ is degraded in S-phase by the CRL4 cdt2 complex after replicative-associated DNA damage (Terai et al, 2013; Zhang et al, 2013). These results suggest that, in human cells, polymerase δ could not be essential for stalled and collapsed replication forks repair.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Proteins PALB2 and BRCA2 Stimulate Polymerase η in Recombination-Associated DNA Synthesis at Blocked Replication Forks

Buisson¹,

Joshi²,

Pauty³

et al. 2014

Cell Reports

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Summary One envisioned function of homologous recombination (HR) is to find a template for DNA synthesis from the resected 3′-OH molecules that occur during double-strand break (DSB) repair at broken or stalled replication forks. However, the interplay between DNA synthesis and HR remains poorly understood in higher eukaryotic cells. Here, we reveal new functions for breast cancer proteins BRCA2 and PALB2 at blocked replication forks and show a role for these proteins in stimulating polymerase eta (Polη) to initiate DNA synthesis. PALB2, BRCA2 and Polη co-localize at stalled or collapsed replication forks after hydroxyurea treatment. Moreover, PALB2 and BRCA2 interact with Polη, and are required to sustain the recruitment of Polη at blocked replication forks. PALB2 and BRCA2 stimulate Polη-dependent DNA synthesis on D-loop substrates. We conclude that PALB2 and BRCA2, in addition to their functions in D-loop formation, play crucial roles in the initiation of recombination-associated DNA synthesis by Polη-mediated DNA repair.

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A Novel Function of CRL4Cdt2

Cited by 47 publications

References 81 publications

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

Breast Cancer Proteins PALB2 and BRCA2 Stimulate Polymerase η in Recombination-Associated DNA Synthesis at Blocked Replication Forks

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