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- EMDB-45664: Cryo-EM structure of FAN1-PCNA-DNA in final state -

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Basic information

Entry
Database: EMDB / ID: EMD-45664
TitleCryo-EM structure of FAN1-PCNA-DNA in final state
Map data
Sample
  • Complex: Ternary complex of FAN1-PCNA-DNA in final state
    • DNA: DNA (46-MER) with (CAG)2 extrusion
    • DNA: DNA (40-MER)
    • Protein or peptide: Proliferating cell nuclear antigen
    • Protein or peptide: Fanconi-associated nuclease 1
Keywordsnuclease / CAG expansion / DNA repair / Huntington's disease / DNA BINDING PROTEIN / PROTEIN BINDING
Function / homology
Function and homology information


flap-structured DNA binding / phosphodiesterase I / positive regulation of deoxyribonuclease activity / dinucleotide insertion or deletion binding / PCNA-p21 complex / mitotic telomere maintenance via semi-conservative replication / 5'-flap endonuclease activity / purine-specific mismatch base pair DNA N-glycosylase activity / nuclear lamina / positive regulation of DNA-directed DNA polymerase activity ...flap-structured DNA binding / phosphodiesterase I / positive regulation of deoxyribonuclease activity / dinucleotide insertion or deletion binding / PCNA-p21 complex / mitotic telomere maintenance via semi-conservative replication / 5'-flap endonuclease activity / purine-specific mismatch base pair DNA N-glycosylase activity / nuclear lamina / positive regulation of DNA-directed DNA polymerase activity / Polymerase switching / MutLalpha complex binding / Telomere C-strand (Lagging Strand) Synthesis / Processive synthesis on the lagging strand / PCNA complex / Removal of the Flap Intermediate / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / Processive synthesis on the C-strand of the telomere / Polymerase switching on the C-strand of the telomere / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / Transcription of E2F targets under negative control by DREAM complex / Removal of the Flap Intermediate from the C-strand / ubiquitin-modified protein reader activity / replisome / response to L-glutamate / 5'-3' exonuclease activity / phosphodiesterase I activity / response to dexamethasone / histone acetyltransferase binding / DNA polymerase processivity factor activity / leading strand elongation / G1/S-Specific Transcription / nuclear replication fork / replication fork processing / SUMOylation of DNA replication proteins / PCNA-Dependent Long Patch Base Excision Repair / response to cadmium ion / translesion synthesis / estrous cycle / mismatch repair / interstrand cross-link repair / intercellular bridge / cyclin-dependent protein kinase holoenzyme complex / base-excision repair, gap-filling / DNA polymerase binding / liver regeneration / epithelial cell differentiation / positive regulation of DNA repair / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / Translesion synthesis by REV1 / Translesion synthesis by POLK / Translesion synthesis by POLI / positive regulation of DNA replication / Gap-filling DNA repair synthesis and ligation in GG-NER / replication fork / nuclear estrogen receptor binding / male germ cell nucleus / nucleotide-excision repair / Fanconi Anemia Pathway / Termination of translesion DNA synthesis / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / double-strand break repair via homologous recombination / receptor tyrosine kinase binding / HDR through Homologous Recombination (HRR) / Dual Incision in GG-NER / cellular response to xenobiotic stimulus / cellular response to hydrogen peroxide / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / cellular response to UV / response to estradiol / E3 ubiquitin ligases ubiquitinate target proteins / heart development / chromatin organization / damaged DNA binding / chromosome, telomeric region / nuclear body / cilium / DNA repair / centrosome / chromatin binding / chromatin / protein-containing complex binding / enzyme binding / magnesium ion binding / negative regulation of transcription by RNA polymerase II / extracellular exosome / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
: / : / : / Fanconi-associated nuclease 1, SAP subdomain / Fanconi-associated nuclease 1, TPR domain / Fanconi-associated nuclease 1-like / : / FAN1, HTH domain / VRR-NUC domain / VRR-NUC domain ...: / : / : / Fanconi-associated nuclease 1, SAP subdomain / Fanconi-associated nuclease 1, TPR domain / Fanconi-associated nuclease 1-like / : / FAN1, HTH domain / VRR-NUC domain / VRR-NUC domain / VRR_NUC / Rad18-like CCHC zinc finger / tRNA endonuclease-like domain superfamily / Proliferating cell nuclear antigen signature 2. / Proliferating cell nuclear antigen, PCNA, conserved site / Proliferating cell nuclear antigen signature 1. / Proliferating cell nuclear antigen, PCNA / Proliferating cell nuclear antigen, PCNA, N-terminal / Proliferating cell nuclear antigen, PCNA, C-terminal / Proliferating cell nuclear antigen, N-terminal domain / Proliferating cell nuclear antigen, C-terminal domain / Rad18, zinc finger UBZ4-type / Zinc finger UBZ4-type profile. / :
Similarity search - Domain/homology
Proliferating cell nuclear antigen / Fanconi-associated nuclease 1
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.83 Å
AuthorsFenglin L / Anna P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair.
Authors: F Li / A S Phadte / M Bhatia / S Barndt / A R Monte Carlo Iii / C-F D Hou / R Yang / S Strock / A Pluciennik /
Abstract: FAN1 is a DNA dependent nuclease whose proper function is essential for maintaining human health. For example, a genetic variant in FAN1, Arg507 to His hastens onset of Huntington's disease, a repeat ...FAN1 is a DNA dependent nuclease whose proper function is essential for maintaining human health. For example, a genetic variant in FAN1, Arg507 to His hastens onset of Huntington's disease, a repeat expansion disorder for which there is no cure. How the Arg507His mutation affects FAN1 structure and enzymatic function is unknown. Using cryo-EM and biochemistry, we have discovered that FAN1 arginine 507 is critical for its interaction with PCNA, and mutation of Arg507 to His attenuates assembly of the FAN1-PCNA complex on a disease-relevant extrahelical DNA extrusions formed within DNA repeats. This mutation concomitantly abolishes PCNA-FAN1-dependent cleavage of such extrusions, thus unraveling the molecular basis for a specific mutation in FAN1 that dramatically hastens the onset of Huntington's disease. These results underscore the importance of PCNA to the genome stabilizing function of FAN1.
History
DepositionJul 10, 2024-
Header (metadata) releaseFeb 19, 2025-
Map releaseFeb 19, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45664.png

Downloads & links

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Map

FileDownload / File: emd_45664.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.944 Å		1.07 Å/pix.
x 256 pix.
= 274.944 Å		1.07 Å/pix.
x 256 pix.
= 274.944 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.074 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.21617506 - 0.47618592
Average (Standard dev.)0.00032916854 (±0.014848383)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_45664_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_45664_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of FAN1-PCNA-DNA in final state

EntireName: Ternary complex of FAN1-PCNA-DNA in final state
Components
  • Complex: Ternary complex of FAN1-PCNA-DNA in final state
    • DNA: DNA (46-MER) with (CAG)2 extrusion
    • DNA: DNA (40-MER)
    • Protein or peptide: Proliferating cell nuclear antigen
    • Protein or peptide: Fanconi-associated nuclease 1

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Supramolecule #1: Ternary complex of FAN1-PCNA-DNA in final state

SupramoleculeName: Ternary complex of FAN1-PCNA-DNA in final state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA (46-MER) with (CAG)2 extrusion

MacromoleculeName: DNA (46-MER) with (CAG)2 extrusion / type: dna / ID: 1 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 14.231137 KDa
SequenceString:
(DC)(DG)(DA)(DA)(DT)(DT)(DT)(DC)(DT)(DA) (DG)(DA)(DC)(DT)(DC)(DG)(DA)(DG)(DA)(DT) (DC)(DA)(DG)(DC)(DA)(DG)(DC)(DT)(DG) (DC)(DT)(DA)(DG)(DG)(DT)(DC)(DG)(DA)(DG) (DT) (DC)(DT)(DA)(DG)(DA)(DG)

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Macromolecule #2: DNA (40-MER)

MacromoleculeName: DNA (40-MER) / type: dna / ID: 2 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 12.25689 KDa
SequenceString:
(DC)(DT)(DC)(DT)(DA)(DG)(DA)(DC)(DT)(DC) (DG)(DA)(DC)(DC)(DT)(DA)(DG)(DC)(DA)(DG) (DA)(DT)(DC)(DT)(DC)(DG)(DA)(DG)(DT) (DC)(DT)(DA)(DG)(DA)(DA)(DA)(DT)(DT)(DC) (DG)

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Macromolecule #3: Proliferating cell nuclear antigen

MacromoleculeName: Proliferating cell nuclear antigen / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.795752 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MFEARLVQGS ILKKVLEALK DLINEACWDI SSSGVNLQSM DSSHVSLVQL TLRSEGFDTY RCDRNLAMGV NLTSMSKILK CAGNEDIIT LRAEDNADTL ALVFEAPNQE KVSDYEMKLM DLDVEQLGIP EQEYSCVVKM PSGEFARICR DLSHIGDAVV I SCAKDGVK ...String:
MFEARLVQGS ILKKVLEALK DLINEACWDI SSSGVNLQSM DSSHVSLVQL TLRSEGFDTY RCDRNLAMGV NLTSMSKILK CAGNEDIIT LRAEDNADTL ALVFEAPNQE KVSDYEMKLM DLDVEQLGIP EQEYSCVVKM PSGEFARICR DLSHIGDAVV I SCAKDGVK FSASGELGNG NIKLSQTSNV DKEEEAVTIE MNEPVQLTFA LRYLNFFTKA TPLSSTVTLS MSADVPLVVE YK IADMGHL KYYLAPKIED EEGS

UniProtKB: Proliferating cell nuclear antigen

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Macromolecule #4: Fanconi-associated nuclease 1

MacromoleculeName: Fanconi-associated nuclease 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.856969 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: HPYYLRSFLV VLKTVLENED DMLLFDEQEK GIVTKFYQLS ATGQKLYVRL FQRKLSWIKM TKLEYEEIAL DLTPVIEELT NAGFLQTES ELQELSEVLE LLSAPELKSL AKTFHLVNPN GQKQQLVDAF LKLAKQRSVC TWGKNKPGIG AVILKRAKAL A GQSVRICK ...String:
HPYYLRSFLV VLKTVLENED DMLLFDEQEK GIVTKFYQLS ATGQKLYVRL FQRKLSWIKM TKLEYEEIAL DLTPVIEELT NAGFLQTES ELQELSEVLE LLSAPELKSL AKTFHLVNPN GQKQQLVDAF LKLAKQRSVC TWGKNKPGIG AVILKRAKAL A GQSVRICK GPRAVFSRIL LLFSLTDSME DEDAACGGQG QLSTVLLVNL GRMEFPSYTI NRKTHIFQDR DDLIRYAAAT HM LSDISSA MANGNWEEAK ELAQCAKRDW NRLKNHPSLR CHEDLPLFLR CFTVGWIYTR ILSRFVEILQ RLHMYEEAVR ELE SLLSQR IYCPDSRGRW WDRLALNLHQ HLKRLEPTIK CITEGLADPE VRTGHRLSLY QRAVRLRESP SCKKFKHLFQ QLPE MAVQD VKHVTITGRL CPQRGMCKSV FVMEAGEAAD PTTVLCSVEE LALAHYRRSG FDQGIHGEGS TFSTLYGLLL WDIIF MDGI PDVFRNACQA FPLDLCTDSF FTSRRPALEA RLQLIHDAPE ESLRAWVAAT WHEQEGRVAS LVSWDRFTSL QQAQDL VSC LGGPVLSGVC RHLAADFRHC RGGLPDLVVW NSQSRHFKLV EVKGPNDRLS HKQMIWLAEL QKLGAEVEVC HVVAVG

UniProtKB: Fanconi-associated nuclease 1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.83 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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