Structure of the processive human Pol δ holoenzyme

Lancey, Claudia; Tehseen, Muhammad; Raducanu, Vlad-Stefan; Rashid, Fahad; Merino, Nekane; Ragan, Timothy J.; Savva, Christos G.; Zaher, Manal S.; Shirbini, Afnan; Blanco, Francisco J.; Hamdan, Samir M.; Biasio, Alfredo De

doi:10.1038/s41467-020-14898-6

Cited by 124 publications

(131 citation statements)

References 78 publications

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“…It was proposed that these conformations represent inactive complexes, with FEN1 required to swing through a flexible hinge to acquire a DNA-cleavage competent position. This was the only structure of a full-length protein bound to PCNA until the recent cryo-EM structure of PCNA-DNA-Pol δ and FEN1 [59]. The reconstruction fitting a defined FEN1 conformer comprises~20% of the particle dataset, while the reconstruction from the entire dataset shows no significant density at the FEN1 binding site.…”

Section: Simultaneous Interactions With the Pcna Ring: The Tool-beltmentioning

confidence: 99%

“…An alternative PCNA binding motif has been found: the AlkB homologue PCNA interacting motif (APIM), which comprises only five amino acids with the sequence [59,60]. The crystal structure of PCNA in complex with APIM peptides showed a similar binding mode to the PIP motif, despite having a highly divergent sequence from the canonical PIP box ( Figure 5).…”

Section: Revisiting the Pip Box Definitionmentioning

confidence: 99%

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Human PCNA Structure, Function and Interactions

2020

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Proliferating cell nuclear antigen (PCNA) is an essential factor in DNA replication and repair. It forms a homotrimeric ring that embraces the DNA and slides along it, anchoring DNA polymerases and other DNA editing enzymes. It also interacts with regulatory proteins through a sequence motif known as PCNA Interacting Protein box (PIP-box). We here review the latest contributions to knowledge regarding the structure-function relationships in human PCNA, particularly the mechanism of sliding, and of the molecular recognition of canonical and non-canonical PIP motifs. The unique binding mode of the oncogene p15 is described in detail, and the implications of the recently discovered structure of PCNA bound to polymerase δ are discussed. The study of the post-translational modifications of PCNA and its partners may yield therapeutic opportunities in cancer treatment, in addition to illuminating the way PCNA coordinates the dynamic exchange of its many partners in DNA replication and repair.

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Section: Simultaneous Interactions With the Pcna Ring: The Tool-beltmentioning

confidence: 99%

Section: Revisiting the Pip Box Definitionmentioning

confidence: 99%

Human PCNA Structure, Function and Interactions

2020

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“…The structures of yeast and human pols appear to be similar in general features but differ in nuances. For example, human pol δ has an additional small subunit, p12 (Table 1) hypothesized to regulate pol δ activity during normal replication versus conditions of DNA damage or replicative stress [61,68]. The catalytic subunit of human pol ζ has extended the N-terminal part of unknown significance ( Table 1, Figures 1 and 3).…”

Section: Progress On the Structure-function Of B-family Dna Polymerasmentioning

confidence: 99%

“…primase-pol α[56][57][58], yeast and human pol δ[59][60][61], yeast pol ε alone or in complex with CMG[62][63][64][65], yeast pol ζ[66] (Figure 3).…”

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confidence: 99%

DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer

Pavlov

Zhuk

Stepchenkova

2020

Cancers

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Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication fork organization. The principal idea of participation of different polymerases in specific transactions at the fork proposed by Morrison and coauthors 30 years ago and later named “division of labor,” remains standing, with an amendment of the broader role of polymerase δ in the replication of both the lagging and leading DNA strands. However, cancer-associated mutations predominantly affect the catalytic subunit of polymerase ε that participates in leading strand DNA synthesis. We analyze how new findings in the DNA replication field help elucidate the polymerase variants’ effects on cancer.

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“…The PDB files for the five POLD1 domains (6s1m, 6s1n, 6s1o, 6tny, 6tnz) ( 29 ) were downloaded from the Protein data bank database (PDB, ) ( 30 ). The sdf file of RSV was downloaded from the PubChem database ( ) and converted to pdb using Open Babel ( 31 ).…”

Section: Methodsmentioning

confidence: 99%

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression

et al. 2021

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Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, in which POLD1 may serve as a potential target. However, the anticancer mechanism of RSV on triple negative breast cancer (TNBC) remains unclear. In the present study, the antitumor effects and mechanism of RSV on TNBC cells were analyzed by RNA sequencing (RNA-seq), which was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, and hematoxylin-eosin (HE) staining. According to the corresponding findings, the survival rate of MDA-MB-231 cells gradually decreased as RSV treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected by RSV treatment were mainly involved in apoptosis and the p53 signaling pathway. Moreover, apoptosis of MDA-MB-231 cells induced by RSV was observed to be mainly mediated by POLD1. When treated with RSV, the expression levels of full length PARP1, PCNA, and BCL-2 were found to be significantly reduced, and the expression level of Cleaved-PARP1 as well as Cleaved-Caspase3 increased significantly. Additionally, the mRNA expression of POLD1 was significantly reduced after treatment with RSV, and the protein expression level was also inhibited by RSV in a concentration-dependent manner. The prediction of domain interaction suggested that RSV may bind to at least five functional domains of the POLD1 protein (6s1m, 6s1n, 6s1o, 6tny and 6tnz). Furthermore, after RSV treatment, the anti-apoptotic index (PCNA, BCL-2) of MDA-MB-231 cells was found to decrease while the apoptosis index (caspase3) increased. Moreover, the overexpression of POLD1 reduced the extent of apoptosis observed in MDA-MB-231 cells following RSV treatment. Moreover, animal experimental results showed that RSV had a significant inhibitory effect on the growth of live tumors, while POLD1 overexpression was shown to antagonize this inhibitory effect. Accordingly, this study’s findings reveal that RSV may promote the apoptosis of TNBC cells by reducing the expression of POLD1 to activate the apoptotic pathway, which may serve as a potential therapy for the treatment of TNBC.

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Structure of the processive human Pol δ holoenzyme

Cited by 124 publications

References 78 publications

Human PCNA Structure, Function and Interactions

Human PCNA Structure, Function and Interactions

DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression

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