The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

Lee, Marietta Y.W.T.; Zhang, Sufang; Lin, Shin; Wang, Xiaoxiao; Darzynkiewicz, Zbigniew; Zhang, Zhongtao; Lee, Ernest Y.C.

doi:10.4161/cc.27407

Cited by 32 publications

(69 citation statements)

References 95 publications

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“…Depletion of either of the two isoforms of Cul4 [115] also suppresses UV-induced p12 degradation with similar time courses as for p21 [59,61]. The NEDD8-activating enzyme (NAE) is required for Cullin ligase activity; the NAE inhibitor, MLN4924 [116], blocks UV and IR degradation of p12 [59,77]. CRL4 Cdt2 has also been shown to be required for the UV-induced inhibition of DNA synthesis; furthermore, replication fork progression is inhibited and is dependent on p12 degradation [77].…”

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 92%

“…Mutation of the PIP-degron of p12 reduces its UV-induced degradation. Depletion of either of the two isoforms of Cul4 [115] also suppresses UV-induced p12 degradation with similar time courses as for p21 [59,61]. The NEDD8-activating enzyme (NAE) is required for Cullin ligase activity; the NAE inhibitor, MLN4924 [116], blocks UV and IR degradation of p12 [59,77].…”

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

“…These studies showed that p12 levels were reduced during S phase and returned to basal levels during G2/M [59,61]. Depletion of CRL4 Cdt2 isoforms reduced the S phase degradation of p12 [59,61].…”

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

“…There is a surprising paucity of literature on the control of eukaryotic DNA polymerase activities by posttranslational modification [2,48,57,58]. The p12 subunit has emerged as a center point for regulation of Pol δ [58,59]. The discovery that the p12 subunit is rapidly degraded by ubiquitination and proteasomal degradation in response to DNA damage opened a new window on the regulation of Pol δ [60].…”

Section: Brief Historical Backgroundmentioning

confidence: 99%

“…CRL4 Cdt2 was found to target p12 for degradation in response to UV, and also mediates the degradation of p12 before entry into S phase [59,61]. The CRL4 Cdt2 ubiquitin ligase plays a critical role in the prevention of re-replication, as the "master coordinator of cell cycle progression and genome stability" [103].…”

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

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Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Lee

Wang

Zhang

et al. 2017

Preprint

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This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, PDIP46 and PDIP38, both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the splicesosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, Mdm2 alternative splicing and the regulation of the Nox4 NADPH oxidase.

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Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 92%

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

Section: Brief Historical Backgroundmentioning

confidence: 99%

Section: Degradation Of P12 By Crl4 Cdt2mentioning

confidence: 99%

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Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Lee

Wang

Zhang

et al. 2017

Preprint

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Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation

Liu

et al. 2020

Molec Gen & Gen Med

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Background Fanconi anemia (FA) is a rare recessive disease characterized by DNA damage repair deficiency, and DNA polymerase δ (whose catalytic subunit is encoded by POLD1 , also known as CDC2 ) is closely related to DNA damage repair. Our previous study identified a novel POLD1 missense mutation c.56G>A (p. Arg19>His) in FA family members. However, the function of the POLD1 missense mutation is currently unknown. This study aimed to uncover the biological function of the POLD1 missense mutation. Methods Stable cell lines overexpressing wild‐type POLD1 or mutant POLD1 (c.56G>A, p.Arg19His) were constructed by lentivirus infection. Cell growth curve analysis, cell cycle analysis, and a comet assay were used to analyze the function of the POLD1 mutation. Results The growth and proliferative ability of the cells with POLD1 mutation was decreased significantly compared with those of the wild‐type cells (Student's t test, p < .05). The percentage of cells in the G0/G1 phase increased, and the percentage of cells in the S phase decreased significantly when POLD1 was mutated (Student's t test, p < .05). Moreover, the Olive tail moment value of the cells with the POLD1 mutation was significantly higher than that of the cells with wild‐type POLD1 after H 2 O 2 treatment. Conclusions The POLD1 mutation inhibited cell proliferation, slowed cell cycle progression, and reduced DNA damage repair.

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UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

Fan,

You,

Jiang

et al. 2024

Cell. Mol. Life Sci.

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Background The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. Method Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. Result We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. Conclusion These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

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The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

Cited by 32 publications

References 95 publications

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

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The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

Cited by 32 publications

References 95 publications

Regulation and Modulation of Human DNA Polymerase &delta; Activity and Function

Regulation and Modulation of Human DNA Polymerase &delta; Activity and Function

Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells

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Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Regulation and Modulation of Human DNA Polymerase δ Activity and Function