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

Pavlov, Youri I.; Zhuk, Anna S.; Stepchenkova, Elena I.

doi:10.3390/cancers12123489

Cited by 17 publications

(15 citation statements)

References 150 publications

(197 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 18 While genomic alteration is deleterious to cells, in certain contexts, it facilitates rapid adaptation to unfavorable environments and is often considered a hallmark of pathogenicity, drug resistance, and cancer development. 19 , 20 The opportunistic fungal pathogen C. albicans has emerged as an ideal model organism to study the association of genome dynamics with its pathogenesis. Since Polδ takes part in several DNA transaction processes, it might play a key role in the genome stability of C. albicans .…”

Section: Introductionmentioning

confidence: 99%

Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

et al. 2023

View full text Add to dashboard Cite

Candida albicans is a pathobiont that inflicts serious bloodstream fungal infections in individuals with compromised immunity and gut dysbiosis. Genomic diversity in the form of copy number alteration, ploidy variation, and loss of heterozygosity as an adaptive mechanism to adverse environments is frequently observed in C. albicans . Such genomic variations also confer a varied degree of fungal virulence and drug resistance, yet the factors propelling these are not completely understood. DNA polymerase delta (Polδ) is an essential replicative DNA polymerase in the eukaryotic cell and is yet to be characterized in C. albicans . Therefore, this study was designed to gain insights into the role of Polδ, especially its non-essential subunit Pol32, in the genome plasticity and life cycle of C. albicans . PCNA, the DNA clamp, recruits Polδ to the replication fork for processive DNA replication. Unlike in Saccharomyces cerevisiae , the PCNA interaction protein (PIP) motif of CaPol32 is critical for Polδ’s activity during DNA replication. Our comparative genetic analyses and whole-genome sequencing of POL32 proficient and deficient C. albicans cells revealed a critical role of Pol32 in DNA replication, cell cycle progression, and genome stability as SNPs, indels, and repeat variations were largely accumulated in pol32 null strain. The loss of pol32 in C. albicans conferred cell wall deformity; Hsp90 mediated azoles resistance, biofilm development, and a complete attenuation of virulence in an animal model of systemic candidiasis. Thus, although Pol32 is dispensable for cell survival, its function is essential for C. albicans pathogenesis; and we discuss its translational implications in antifungal drugs and whole-cell vaccine development.

show abstract

Section: Introductionmentioning

confidence: 99%

Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

et al. 2023

View full text Add to dashboard Cite

show abstract

“…(1) (8) (9) (10) Recently mutations have been identified in the pol/exo subunit of both DNA polymerase δ and ε that appear to be causative for the generation of tumours (reviewed in (11) (12) (13). These were originally seen in colon and endometrial cancer, but more recently have also been reported in other cancers.…”

Section: Introductionmentioning

confidence: 99%

A simple bypass assay for DNA polymerases shows hypermutating variants associated with cancer show mechanistic differences in vitro

Crevel

Kearsey

Cotterill

2022

Preprint

View full text Add to dashboard Cite

Errors made by DNA polymerases contribute to both natural variation and, in extreme cases, to genome instability and its associated diseases. Recently the importance of polymerase misincorporation in disease has been highlighted by the identification of cancer-associated polymerase variants and the recognition that a subgroup of these variants have a hypermutation phenotype in tumours. We have developed a bypass assay to rapidly determine the tendency of a polymerase to misincorporate in vitro. We have used the assay to compare misincorporation by wild-type, exonuclease defective and two hypermutating DNA polymerase e variants, P286R and V411L. The assay clearly distinguished between the misincorporation rates of wild type, exonuclease dead and P286R polymerases. However, the V411L polymerase showed different misincorporation characteristics to P286R, suggesting that these variants cause hypermutation by different mechanisms. Using this assay misincorporation opposite a templated C nucleotide was consistently higher than for other nucleotides, and this caused predominantly C to T transitions. This is consistent with the observation that C to T transitions are commonly seen in POLE mutant tumours.

show abstract

“…Pol ζ, previously thought to be a two-subunit enzyme [ 34 ], is actually a four-subunit enzyme containing the catalytic subunit Rev3 (for protein nomenclature, see [ 38 ]), consisting of the N-terminal region, catalytic core, and C-terminus domain (CTD) containing a 4Fe-4S cluster, and the accessory subunits Rev7, Pol31, and Pol32 [ 39 , 40 , 41 , 42 ] ( Figure 1 A). The latter two subunits are shared with the main replicative DNA pol δ. Pol ζ also binds another TLS pol, Rev1, forming a five-subunit complex [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

DNA Polymerase ζ without the C-Terminus of Catalytic Subunit Rev3 Retains Characteristic Activity, but Alters Mutation Specificity of Ultraviolet Radiation in Yeast

Siebler

Cui

Hill

et al. 2022

Genes

Self Cite

View full text Add to dashboard Cite

DNA polymerase ζ (pol ζ) plays a central role in replicating damaged genomic DNA. When DNA synthesis stalls at a lesion, it participates in translesion DNA synthesis (TLS), which helps replication proceed. TLS prevents cell death at the expense of new mutations. The current model indicates that pol ζ-dependent TLS events are mediated by Pol31/Pol32 pol ζ subunits, which are shared with replicative polymerase pol δ. Surprisingly, we found that the mutant rev3-ΔC in yeast, which lacks the C-terminal domain (CTD) of the catalytic subunit of pol ζ and, thus, the platform for interaction with Pol31/Pol32, retains most pol ζ functions. To understand the underlying mechanisms, we studied TLS in normal templates or templates with abasic sites in vitro in primer extension reactions with purified four-subunit pol ζ versus pol ζ with Rev3-ΔC. We also examined the specificity of ultraviolet radiation (UVR)-induced mutagenesis in the rev3-ΔC strains. We found that the absence of Rev3 CTD reduces activity levels, but does not alter the basic biochemical properties of pol ζ, and alters the mutation spectrum only at high doses of UVR, alluding to the existence of mechanisms of recruitment of pol ζ to UVR-damaged sites independent of the interaction of Pol31/Pol32 with the CTD of Rev3.

show abstract

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

Cited by 17 publications

References 150 publications

Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

A simple bypass assay for DNA polymerases shows hypermutating variants associated with cancer show mechanistic differences in vitro

DNA Polymerase ζ without the C-Terminus of Catalytic Subunit Rev3 Retains Characteristic Activity, but Alters Mutation Specificity of Ultraviolet Radiation in Yeast

Contact Info

Product

Resources

About