POLE · DNA Polymerase ε Catalytic Subunit

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POLE

DNA Polymerase ε · Catalytic Subunit · p261

CHR 12q24.33

2,286 AA

~261 kDa

UniProt Q07864

Functional domains N → C

N-terminal domain

res. 1–280

Structural scaffolding region preceding the catalytic core. Contains residues affected by the ultra-rare c.138del germline truncation.

NTD

3′→5′ Exonuclease

res. 268–471

Proofreading domain that excises misincorporated nucleotides. Contains catalytic residues D275, E277, D368, D370 (ExoI/II/III motifs) coordinating two divalent metal ions. Primary site of cancer-driving POLE mutations.

EXO

Palm subdomain

res. 600–870

Houses the polymerase active site. Conserved aspartate carboxylates (D640, D642 motif A; D860 motif C) coordinate two Mg²⁺ ions for phosphodiester bond formation via the two-metal-ion catalytic mechanism.

PALM

Processivity (P) domain

res. 700–760

Pol ε-specific insertion between Palm and Fingers that distinguishes it from all other B-family polymerases. Houses the [4Fe-4S] iron-sulfur cluster (CysX motif) essential for polymerase activity, contacts the nascent duplex, and forms one of three PCNA contact surfaces.

P-DOM

Fingers subdomain

res. 870–1020

Predominantly α-helical region. The O-helix undergoes a 28°/19 Å conformational closure upon dNTP binding (open → ajar → closed; PDB 9F6D/9F6E/9F6F), ensuring Watson–Crick base-pair geometry. Rate-limiting step for nucleotide incorporation and the structural basis of replicative fidelity.

FNG

Thumb subdomain

res. 1020–1190

Helical bundle that grips the minor groove of the nascent duplex DNA product. Contacts extend ~8 bp into the product duplex. The Thumb insertion (res. 1102–1122) forms a second PCNA contact, contributing to the tripartite interface that makes Pol ε–PCNA resistant to displacement by Pol δ and FEN1.

THM

Inactive Pol module

res. 1198–1900

Non-catalytic B-family polymerase fold (the “Pol2 module” of Yuan et al. 2020) that retains the canonical Palm/Fingers/Thumb architecture but has lost all enzymatic activity. Serves as the structural platform for POLE2/3/4 accessory subunit assembly and bridges the catalytic N-terminal half to the CTD zinc-finger appendix.

INACT

C-terminal domain

res. 1900–2286

Contains CysA and CysB zinc-finger motifs that serve as the structural platform for binding accessory subunits POLE2, POLE3, and POLE4, completing the heterotetrameric holoenzyme.

CTD

Display controls

Template / nascent DNA

Catalytic Mg²⁺ ions

Incoming dNTP

Domain labels

Mutation hotspots

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Molecular envelope

H-bonds (i→i+4)

β-sheet H-bonds

Zn-finger motifs

[4Fe-4S] cluster

Exonuclease active site

Accessory subunits

PCNA sliding clamp

Exo↔Pol shuttling

Color mode approx.

Color scheme

Tools

Navigation

Mol* Coordinate Viewer

PDB 9F6D · real atomic coordinates · DSSP · B-factors

AlphaFold Predicted Structure

Full-length 2,286 AA · pLDDT confidence · AlphaFold v4

Variant Catalogue

ACMG classification · SBS signatures · ΔΔG

c.138del Frameshift Viewer

p.Leu46Phefs*8 · germline truncation analysis

Model note

This is a procedural schematic, not an atomic-coordinate rendering. Ribbon geometry is algorithmically generated to illustrate domain topology. Color modes (B-factor, conservation, charge) display approximate values, not crystallographic or computed data. For coordinate-derived analysis, use the Mol* Coordinate Viewer (PDB 9F6D, Roske & Yeeles 2024) or load into Mol* / PyMOL.

structure · live

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~50 Å

ribbon · cartoon CPK · active site

Locus & identity

Gene

POLE (ENSG00000177084)

Cytogenetic location

12q24.33

Genomic span

~64 kb · 50 exons

Polymerase family

B-family · Pol ε

Holoenzyme partners

POLE2 · POLE3 · POLE4

PDB structures

9F6D · 9F6E · 9F6F · 9B8S · 4M8O

Function · in vivo

Pol ε performs leading-strand synthesis at the eukaryotic replisome, copying the template 3′→5′ while extending the nascent strand 5′→3′ at >50 nt/s. Base-substitution error rate approaches 10−7 per nucleotide incorporated.

The intrinsic 3′→5′ exonuclease excises misincorporated nucleotides via an intramolecular shuttling mechanism, switching the primer terminus between the polymerase and exonuclease active sites separated by ~40 Å (Roske & Yeeles 2024). The mismatch-recognition pathway proceeds through four structurally resolved states: post-insertion → arrest → frayed substrate → mismatch excision.

Pathogenic hotspots

P286R

EXO · ultra-mutator

Most frequent cancer-associated POLE mutation. Pro→Arg substitution in ExoII motif disrupts the proofreading active site, causing an ultra-mutation phenotype (TMB >100 mut/Mb) in colorectal & endometrial carcinoma.

V411L

EXO · proofreading-deficient

Recurrent exonuclease-domain mutation that abolishes editing capacity. Associated with microsatellite-stable tumours with very high mutational burden, often exceeding 100 mut/Mb.

S297F

EXO · germline / Lynch-like

Germline variant in the ExoI motif; predisposes to polymerase-proofreading-associated polyposis (PPAP). Autosomal dominant with variable penetrance for colorectal adenomas.

F367S

EXO · germline PPAP

Adjacent to ExoIII catalytic residue D368. Germline variant associated with polymerase proofreading-associated polyposis.

View all 9 variants with ACMG classification →

Catalytic mechanism

Two-metal-ion catalysis: Metal A (Mg²⁺) lowers the pKa of the primer 3′-OH, generating the nucleophile. Metal B (Mg²⁺) coordinates the β,γ-phosphates of the incoming dNTP and stabilizes the pentacoordinate transition state. Both metals are chelated by conserved aspartate carboxylates (D640, D642, D860).

References

        Roske & Yeeles, NSMB 31:1921 (2024)

        He et al., Nat Commun 15:7847 (2024)

        Mur et al., Genome Med 15:85 (2023)

        Yuan et al., Nat Commun 11:3156 (2020)

        Coorens et al., Nat Genet 53:1434 (2021)

        Hogg et al., NSMB 21:49 (2014)

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