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- PDB-9gy0: Cryo_EM structure of human FAN1 R507H mutant in complex with 5' f... -

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Basic information

Entry
Database: PDB / ID: 9gy0
TitleCryo_EM structure of human FAN1 R507H mutant in complex with 5' flap DNA substrate and PCNA
Components
  • DNA (Continuous)
  • DNA (Post-Nick)
  • DNA (Pre-Nick)
  • Fanconi-associated nuclease 1
  • Proliferating cell nuclear antigen
KeywordsDNA BINDING PROTEIN / FAN1 R507H / PCNA
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 / interstrand cross-link repair / mismatch 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
DNA / DNA (> 10) / Proliferating cell nuclear antigen / Fanconi-associated nuclease 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsJeyasankar, G. / Salerno-Kochan, A. / Thomsen, M.
Funding support United States, 1items
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, T.F. / Boudet, J. / Prasad, B.C.
History
DepositionOct 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.2Jul 9, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 9, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fanconi-associated nuclease 1
B: DNA (Continuous)
C: DNA (Pre-Nick)
D: DNA (Post-Nick)
E: Proliferating cell nuclear antigen
F: Proliferating cell nuclear antigen
G: Proliferating cell nuclear antigen
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,9228
Polymers228,8827
Non-polymers401
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 4 molecules AEFG

#1: Protein Fanconi-associated nuclease 1 / FANCD2/FANCI-associated nuclease 1 / hFAN1 / Myotubularin-related protein 15


Mass: 114705.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAN1, KIAA1018, MTMR15 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y2M0, Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters, phosphodiesterase I
#5: Protein Proliferating cell nuclear antigen / PCNA / Cyclin


Mass: 28949.912 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PCNA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P12004

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DNA chain , 3 types, 3 molecules BCD

#2: DNA chain DNA (Continuous)


Mass: 12154.740 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: DNA chain DNA (Pre-Nick)


Mass: 8618.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#4: DNA chain DNA (Post-Nick)


Mass: 6554.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 1 types, 1 molecules

#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of FAN1 R507H-PCNA-DNACOMPLEX#1-#50MULTIPLE SOURCES
2FAN1 R507H-PCNACOMPLEX#1, #51RECOMBINANT
3DNACOMPLEX#2-#41NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33synthetic construct (others)32630
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 487606 / Symmetry type: POINT

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