ADP-ribose contributions to genome stability and PARP enzyme trapping on sites of DNA damage; paradigm shifts for a coming-of-age modification

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(12), С. 105397 - 105397

Опубликована: Окт. 28, 2023

ADP-ribose is a versatile modification that plays critical role in diverse cellular processes. The addition of this catalyzed by ADP-ribosyltransferases, among which notable poly(ADP-ribose) polymerase (PARP) enzymes are intimately involved the maintenance genome integrity. modifications during DNA damage repair significant interest for proper development PARP inhibitors targeted toward treatment diseases caused genomic instability. More specifically, promoting persistence on lesions, termed "trapping," considered desirable characteristic. In review, we discuss key classes proteins signaling (writers, readers, and erasers) with focus those An overview factors modulate PARP1 PARP2 at sites lesions also discussed. Finally, clarify aspects trapping model light recent studies characterize kinetics recruitment lesions. These findings suggest could be as continuous molecules to rather than physical stalling molecules. Recent novel research tools have elevated level understanding ADP-ribosylation, marking coming-of-age interesting modification. carries necessary information many processes within cell maintaining its stability importance ensure viability. Genome instability can arise from endogenous causes, such normal transactions (replication, transcription, recombination), but exogenous like external damaging agents (1Chatterjee N. Walker G.C. Mechanisms damage, repair, mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref PubMed Scopus (957) Google Scholar). sheer number each human experiences daily (approximately 70,000 lesions) (2Lindahl T. Barnes D.E. Repair damage.Cold Spring Harb. Symp. Quant. Biol. 2000; 65: 127-133Crossref Scholar) highlights heavy demand put mechanisms. 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(PARPi) important biology several PARPi approved use cancer treatments. covers knowledge mode action, particular clarifying enigmatic process "trapping." ADP-ribosyltransferase (ART) take group NAD+ attach it macromolecules. Proteins modified amino sidechains, Glu, Asp, Ser, Arg, Cys Nucleic receive phosphorylated termini nucleobases diphtheria toxin-like family, containing mammalian enzymes, defined H-Y-[E/D/Q] signature motif their binding 1B). active site composed "donor" split into nicotinamide pocket, catalytic triad located, adenine pocket (7Alemasova effectively holds moiety will attached either target protein/nucleic chain undergoing elongation. elongation requires presence "acceptor" moiety, already target, new added most members family do not catalyze PARylation, they possess sites. include PARP1, PARP2, TNKS1 (PARP5a), TNKS2 (PARP5b) 1C). PARP3 participates catalyzes ADPr, mono-ADP-ribosylation (MARylation). 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While steered automodifies residues, namely S499, S507, S519 (42Prokhorova Smith Zentout Schutzenhofer al.Serine-linked auto-modification inhibitor response.Nat. 4055Crossref (44) Mutating was shown retain longer suggesting likely needed timely release process. highly negatively charged PTM, charge repulsion driving force (43Murai Huang S.Y. Das B.B. Renaud Doroshow J.H. al.Trapping clinical inhibitors.Cancer 72: 5588-5599Crossref (1497) 44Murai Ji Takeda al.Stereospecific BMN 673 olaparib rucaparib.Mol. Cancer Ther. 2014; 433-443Crossref (565) enacting possible. Another well-studied member closest homolog contrast only short, unstructured N-terminal (NTR) accompany (45Riccio Cingolani PARP-2 requirements localization damage.Nucleic 44: 1691-1702Crossref Also, unlike navigates chromatin. mostly mediated 5′ (46Langelier PARP-3 selective

Язык: Английский

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BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve

Язык: Английский

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KH-like Domains in PARP9/DTX3L and PARP14 Coordinate Protein–Protein Interactions to Promote Cancer Cell Survival

Journal of Molecular Biology, Год журнала: 2024, Номер 436(4), С. 168434 - 168434

Опубликована: Янв. 4, 2024

Certain members of the ADP-ribosyltransferase superfamily (ARTD or PARP enzymes) catalyse ADP-ribosylation in response to cellular stress, DNA damage and viral infection are upregulated various tumours tolerate increased stress. PARP9, its binding partner DTX3L PARP14 protein levels significantly correlated head neck squamous cell carcinoma (HNSCC) other tumour types though a mechanism where PARP9/DTX3L regulates post-transcriptionally. Depleting expression HNSCC HeLa lines decreases survival through reduction proliferation an increase apoptosis. A partial rescue was achieved by expressing truncation containing predicted eukaryotic type I KH domain. KH-like domains were also found PARP9 contributed protein-protein interactions between PARP9-DTX3L PARP14-DTX3L. Homodimerization coordinated domain disrupted site-specific mutation. Although, promoted did not require activity, interaction vitro suppressed auto-ADP-ribosylation trans-ADP-ribosylation DTX3L. In summary, we characterised PARP9-DTX3L-PARP14 important pro-survival signalling cells, albeit catalytically independent fashion.

Язык: Английский

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Regulation of and challenges in targeting NAD+ metabolism

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(10), С. 822 - 840

Опубликована: Июль 18, 2024

Язык: Английский

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A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114234 - 114234

Опубликована: Май 1, 2024

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) not only suppress PARP1 catalytic activity but also prolong its association to damaged chromatin. Here, through live-cell imaging, we quantify the alterations in dynamics and elicited by seven PARPis over a wide range of concentrations deliver unified mechanism PARPi-induced chromatin retention. We find that gross retention at DNA damage sites is jointly governed inhibition allosteric trapping, albeit strictly independent manner—catalytic causes multiple unproductive binding-dissociation cycles PARP1, while trapping prolongs lesion-bound state greatly increase overall Importantly, stronger produces greater temporal shifts downstream repair events superior cytotoxicity, highlighting retention, complex precisely quantifiable characteristic PARPis, as valuable biomarker for PARPi efficacy. Our approach can be promptly repurposed interrogating properties DNA-repair-targeting compounds beyond PARPis.

Язык: Английский

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