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- PDB-9eoa: Cryo_EM structure of human FAN1 in complex with 5' flap DNA subst... -

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Basic information

Entry
Database: PDB / ID: 9eoa
TitleCryo_EM structure of human FAN1 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 / 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 / Processive synthesis on the C-strand of the telomere / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / 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) / Removal of the Flap Intermediate from the C-strand / ubiquitin-modified protein reader activity / Transcription of E2F targets under negative control by DREAM complex / replisome / 5'-3' exonuclease activity / phosphodiesterase I activity / response to L-glutamate / histone acetyltransferase binding / DNA polymerase processivity factor activity / leading strand elongation / G1/S-Specific Transcription / response to dexamethasone / replication fork processing / nuclear replication fork / SUMOylation of DNA replication proteins / PCNA-Dependent Long Patch Base Excision Repair / mismatch repair / translesion synthesis / intercellular bridge / interstrand cross-link repair / response to cadmium ion / estrous cycle / cyclin-dependent protein kinase holoenzyme complex / base-excision repair, gap-filling / DNA polymerase binding / epithelial cell differentiation / positive regulation of DNA repair / male germ cell nucleus / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / Translesion synthesis by REV1 / Translesion synthesis by POLK / liver regeneration / replication fork / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / positive regulation of DNA replication / nuclear estrogen receptor binding / nucleotide-excision repair / Fanconi Anemia Pathway / Termination of translesion DNA synthesis / Recognition of DNA damage by PCNA-containing replication complex / double-strand break repair via homologous recombination / Translesion Synthesis by POLH / receptor tyrosine kinase binding / HDR through Homologous Recombination (HRR) / Dual Incision in GG-NER / cellular response to hydrogen peroxide / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / cellular response to UV / cellular response to xenobiotic stimulus / response to estradiol / E3 ubiquitin ligases ubiquitinate target proteins / heart development / cilium / damaged DNA binding / chromosome, telomeric region / nuclear body / DNA repair / centrosome / chromatin binding / protein-containing complex binding / chromatin / enzyme binding / negative regulation of transcription by RNA polymerase II / magnesium ion binding / 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: 3.27 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
DepositionMar 14, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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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)
F: Proliferating cell nuclear antigen
G: Proliferating cell nuclear antigen
H: Proliferating cell nuclear antigen


Theoretical massNumber of molelcules
Total (without water)184,7927
Polymers184,7927
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 72629.703 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
#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)
#5: Protein Proliferating cell nuclear antigen / PCNA / Cyclin


Mass: 28278.309 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
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-PCNA-DNACOMPLEXall0MULTIPLE SOURCES
2FAN1-PCNACOMPLEX#1-#21RECOMBINANT
3DNACOMPLEX#3-#51RECOMBINANT
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: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 700432 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412128
ELECTRON MICROSCOPYf_angle_d0.65716658
ELECTRON MICROSCOPYf_dihedral_angle_d18.5772089
ELECTRON MICROSCOPYf_chiral_restr0.0431922
ELECTRON MICROSCOPYf_plane_restr0.0041905

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