Cooperative dynamics of PARP-1 zinc-finger domains in the detection of DNA single-strand breaks.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 10 2024
06 10 2024
Historique:
received:
03
06
2024
accepted:
19
09
2024
medline:
7
10
2024
pubmed:
7
10
2024
entrez:
6
10
2024
Statut:
epublish
Résumé
The DNA single-strand break (SSB) repair pathway is initiated by the multifunctional enzyme PARP-1, which recognizes the broken DNA ends by its two zinc-finger domains, Zn1 and Zn2. Despite a number of experiments performed with different DNA configurations and reduced fragments of PARP-1, many details of this interaction that is crucial to the correct initiation of the repair chain are still unclear. We performed Molecular Dynamics (MD) computer simulations of the interaction between the Zn1/Zn2 domains of PARP-1 and a DNA hairpin including a missing nucleotide to simulate the presence of an SSB, a construct used in recent experiments. The role of Zn1 and Zn2 interacting with the SSB ends is studied in detail, both independently and cooperatively. We also explored, PARP-1 operating as a dimer, with the two Zn-fingers coming from two separate copies of the enzyme. By an extensive set of all-atom molecular simulations employing state-of-the art force fields, assisted by empirical docking and free-energy calculations, we conclude that the particular conformation of the DNA hairpin can indeed spontaneously open up by thermal fluctuations, up to extremely kinked deformations. However, such extreme localized deformations are rarely observed in free, long DNA fragments. Protein side-loops make contact with the DNA hairpin grooves, and help Zn2 to penetrate deep in the SSB gap. In this way, Zn2 can interact with the nucleotides opposite to the missing base. Overall, Zn1 plays a secondary role: the crucial factor for the interaction is rather the relative arrangement of the Zn1/Zn2 couple, and their mutual orientation with respect to the
Identifiants
pubmed: 39370429
doi: 10.1038/s41598-024-73707-y
pii: 10.1038/s41598-024-73707-y
doi:
Substances chimiques
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
PARP1 protein, human
EC 2.4.2.30
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23257Subventions
Organisme : Université de Lille
ID : PEARL 238608 "SENESIMEX"
Organisme : Agence Nationale de la Recherche
ID : ANR-21-CE45-0032 DYPROSOME
Organisme : Grand Équipement National De Calcul Intensif
ID : A0130712986 and A0150712986
Informations de copyright
© 2024. The Author(s).
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