DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on nucleic acids

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(2), P. 801 - 815

Published: Nov. 24, 2023

Abstract Although ubiquitylation had traditionally been considered limited to proteins, the discovery of non-proteinaceous substrates (e.g. lipopolysaccharides and adenosine diphosphate ribose (ADPr)) challenged this perspective. Our recent study showed that DTX2 E3 ligase efficiently ubiquitylates ADPr. Here, we show ADPr activity is also present in another DELTEX family member, DTX3L, analysed both as an isolated catalytic fragment full-length PARP9:DTX3L complex, suggesting it a general feature family. Since structural predictions DTX3L possesses single-stranded nucleic acids binding ability given fact have recently emerged for ADP-ribosylation, asked whether E3s might catalyse moiety linked acids. Indeed, are capable ubiquitylating ADP-ribosylated DNA RNA synthesized by PARPs, including PARP14. Furthermore, demonstrate Ub-ADPr-nucleic conjugate can be reversed two groups hydrolases, which remove either whole adduct SARS-CoV-2 Mac1 or PARP14 macrodomain 1) just Ub PLpro). Overall, reveals function presents evidence reversible

Language: Английский

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

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(14)

Published: July 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

Language: Английский

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Regulation of and challenges in targeting NAD+ metabolism

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(10), P. 822 - 840

Published: July 18, 2024

Language: 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, Journal Year: 2024, Volume and Issue: 436(4), P. 168434 - 168434

Published: Jan. 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.

Language: Английский

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

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114234 - 114234

Published: May 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.

Language: Английский

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