Single-molecule analysis of PARP1-G-quadruplex interaction

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

The human genome contains numerous repetitive nucleotide sequences that display a propensity to fold into non-canonical DNA structures including G-quadruplexes (G4s). G4s have both positive and negative impacts on various aspects of nucleic acid metabolism replication, repair RNA transcription. Poly (ADP-ribose) polymerase (PARP1), an important anticancer drug target, has been recently shown bind subset G4s, undergo auto-PARylation. mechanism this interaction, however, is poorly understood. Utilizing Mass Photometry (MP) single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate PARP1 dynamically interacts with 1:1 stoichiometry. Interaction single molecule nicked or containing G4 primer-template junction sufficient activate robust auto-PARylation resulting in the addition poly chains molecular weight several hundred kDa. Pharmacological PARP inhibitors EB-47, Olaparib Veliparib differently affect retention G4-containing compared DNA.

Language: Английский

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Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair, and its inhibition cancer cells may cause cell apoptosis. In this study, we investigated the effects of PARP1 variant, V762A, which is strongly associated with several cancers humans, on by three FDA-approved inhibitors: niraparib, rucaparib, talazoparib. Specifically, compared mutant to that wild-type (WT) PARP1. Additionally, how mutation influences binding these inhibitors Our work suggests while exhibits only minor differences residual fluctuations, backbone deviations, residue motion correlations WT under niraparib rucaparib inhibitions, it shows significant distinct features when inhibited Among talazoparib uniquely lowers average fluctuations than including lower mutant's N- C-terminal residues catalytic domain, conserved H-Y-E traid residues, donor loop (D-loop) are important for catalysis more effectively other inhibitions. However, also significantly enhances destabilizing interactions between site HD domain WT. Further, among disrupts functional terminal regions mutant, otherwise present The do not affect PARP1's essential dynamics. Lastly, bind V762A WT, similar free energies them.

Language: Английский

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The replication stress response: mechanisms and functions

DNA repair, Journal Year: 2025, Volume and Issue: unknown, P. 103834 - 103834

Published: April 1, 2025

Language: Английский

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Novel Strategies in Breast Cancer Management: from Treatment to Long-term Remission

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: unknown, P. 104715 - 104715

Published: April 1, 2025

Language: Английский

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