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- EMDB-19844: Cryo_EM structure of human FAN1 in complex with 5' flap DNA substrate -

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Basic information

Entry
Database: EMDB / ID: EMD-19844
TitleCryo_EM structure of human FAN1 in complex with 5' flap DNA substrate
Map data
Sample
  • Complex: FAN1-DNA complex
    • Complex: FAN1
      • Protein or peptide: Fanconi-associated nuclease 1
    • Complex: DNA
      • DNA: DNA (continuous)
      • DNA: DNA (pre-nick)
      • DNA: DNA (post-nick)
KeywordsDNA BINDING PROTEIN / FAN1
Function / homology
Function and homology information


flap-structured DNA binding / phosphodiesterase I / 5'-flap endonuclease activity / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / ubiquitin-modified protein reader activity / 5'-3' exonuclease activity / phosphodiesterase I activity / interstrand cross-link repair / intercellular bridge / nucleotide-excision repair ...flap-structured DNA binding / phosphodiesterase I / 5'-flap endonuclease activity / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / ubiquitin-modified protein reader activity / 5'-3' exonuclease activity / phosphodiesterase I activity / interstrand cross-link repair / intercellular bridge / nucleotide-excision repair / Fanconi Anemia Pathway / double-strand break repair via homologous recombination / cilium / DNA repair / magnesium ion binding / zinc ion binding / nucleoplasm / 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 / Rad18, zinc finger UBZ4-type / Zinc finger UBZ4-type profile.
Similarity search - Domain/homology
Fanconi-associated nuclease 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsJeyasankar G / Salerno-Kochan A / Thomsen M
Funding support United States, 1 items
OrganizationGrant numberCountry
CHDI Foundation United States
Citation
Journal: Nat Commun / Year: 2025
Title: A FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA.
Authors: Jonas Aretz / Gayathri Jeyasankar / Anna Salerno-Kochan / Maren Thomsen / Gabriel Thieulin-Pardo / Tasir Haque / Edith Monteagudo / Dan Felsenfeld / Michael Finley / Thomas F Vogt / Julien ...Authors: Jonas Aretz / Gayathri Jeyasankar / Anna Salerno-Kochan / Maren Thomsen / Gabriel Thieulin-Pardo / Tasir Haque / Edith Monteagudo / Dan Felsenfeld / Michael Finley / Thomas F Vogt / Julien Boudet / Brinda C Prasad /
Abstract: FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 ...FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 R507H mutation and early disease onset, however the underlying mechanism(s) remains unclear. FAN1 has previously been implicated in modulating triplet repeat expansion in a PCNA dependent manner. To examine the role of PCNA on FAN1 activation, we solved the cryo-EM structures of a PCNA-FAN1-DNA complex. Our findings reveal that the FAN1 R507 residue directly interacts with PCNA D232. Biophysical interaction studies demonstrated that FAN1 enhances the binding affinity of PCNA for DNA, a synergistic effect disrupted in mutants carrying the R507H mutation. In contrast, PCNA does not affect the affinity of FAN1 for DNA but does modulate FAN1 activity upon ternary complex formation. The weakened and functionally altered FAN1 R507H-PCNA-DNA complex may partly impair the FAN1-mediated repair of CAG extrahelical extrusions, providing a potential explanation for the mutation's role in accelerating disease progression.
#1: Journal: Biorxiv / Year: 2024
Title: A FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA
Authors: Aretz J / Jeyasankar G / Salerno-Kochan A / Thomsen M / Thieulin-Pardo G / Haque T / Monteagudo E / Felsenfeld D / Finley M / Vogt TF / Boudet J / Prasad BC
History
DepositionMar 14, 2024-
Header (metadata) releaseJan 29, 2025-
Map releaseJan 29, 2025-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19844.png

Downloads & links

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Map

FileDownload / File: emd_19844.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 300 pix.
= 274.26 Å		0.91 Å/pix.
x 300 pix.
= 274.26 Å		0.91 Å/pix.
x 300 pix.
= 274.26 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9142 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0030493224 - 2.3113985
Average (Standard dev.)0.0007422947 (±0.021048898)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 274.26 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_19844_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19844_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : FAN1-DNA complex

EntireName: FAN1-DNA complex
Components
  • Complex: FAN1-DNA complex
    • Complex: FAN1
      • Protein or peptide: Fanconi-associated nuclease 1
    • Complex: DNA
      • DNA: DNA (continuous)
      • DNA: DNA (pre-nick)
      • DNA: DNA (post-nick)

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Supramolecule #1: FAN1-DNA complex

SupramoleculeName: FAN1-DNA complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: FAN1

SupramoleculeName: FAN1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: DNA

SupramoleculeName: DNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Fanconi-associated nuclease 1

MacromoleculeName: Fanconi-associated nuclease 1 / type: protein_or_peptide / ID: 1 / 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: 72.629703 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 HVV

UniProtKB: Fanconi-associated nuclease 1

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Macromolecule #2: DNA (continuous)

MacromoleculeName: DNA (continuous) / type: dna / ID: 2 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.731217 KDa
SequenceString:
(DC)(DC)(DA)(DG)(DG)(DT)(DC)(DT)(DC)(DG) (DT)(DC)(DC)(DG)(DC)(DG)(DC)(DC)(DA)(DC) (DT)(DC)(DG)(DT)(DG)(DT)(DC)(DC)(DA) (DG)(DC)(DG)

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Macromolecule #3: DNA (pre-nick)

MacromoleculeName: DNA (pre-nick) / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.320815 KDa
SequenceString:
(DG)(DA)(DC)(DA)(DC)(DG)(DA)(DG)(DT)(DG) (DG)(DC)(DT)(DT)

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Macromolecule #4: DNA (post-nick)

MacromoleculeName: DNA (post-nick) / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.277423 KDa
SequenceString:
(DT)(DG)(DC)(DG)(DG)(DA)(DC)(DG)(DA)(DG) (DA)(DC)(DC)(DT)(DG)(DG)(DA)

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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: 8
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 379066
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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